The  acetoacetyl-CoA synthetase  ( AACS ) gene encodes a  protein  of the same name, which converts  acetoacetate  to  acetoacetyl-CoA , and plays a crucial role in  ketone body  utilization and  fatty acid synthesis . The gene is found on human  chromosome 12 .


The AACS protein is a member of the  acetyl-CoA synthetase  family and is involved in cellular energy production,  ketogenesis , and  cholesterol synthesis . [ 5 ]  It is expressed in a wide range of human tissues. [ 6 ]


The protein's function is regulated transcriptionally by  sterol regulatory element-binding protein  (SREBP) and  peroxisome proliferator-activated receptor gamma  (PPARγ). [ 7 ]


This article on a  gene  on human  chromosome 12  is a  stub . You can help Wikipedia by  expanding it .


The  AAMDC  gene encodes an AMDC or  Adipogenesis Associated Mth938 Domain Containing   protein  that is integral to various cellular processes. The protein is involved in  lipid metabolism , specifically  adipogenesis , and plays a role in  signal transduction  as an  oncoprotein . [ 1 ]


The AAMDC protein is found in both the cytoplasmic and nuclear compartments of the cell. [ 2 ]


This article on a  gene  on human  chromosome 11  is a  stub . You can help Wikipedia by  expanding it .


1JU5 ,  2DVJ ,  2EYV ,  2EYW ,  2EYX ,  2EYY ,  2EYZ ,  2MS4


NM_016823 NM_005206


NM_001277219 NM_001277221 NM_133656


NP_005197 NP_058431


NP_001264148 NP_001264150 NP_598417


Adapter molecule crk  also known as  proto-oncogene c-Crk  is a  protein  that in humans is encoded by the  CRK   gene . [ 5 ]


The CRK protein participates in the  Reelin  signaling cascade downstream of  DAB1 . [ 6 ] [ 7 ]


Adapter molecule crk is a member of an  adapter protein  family that binds to several tyrosine-phosphorylated proteins. This protein has several  SH2  and  SH3  domains (src-homology domains) and is involved in several signaling pathways, recruiting cytoplasmic proteins in the vicinity of  tyrosine kinase  through SH2-phosphotyrosine interaction. The  N-terminal  SH2 domain of this protein functions as a positive regulator of transformation whereas the  C-terminal  SH3 domain functions as a negative regulator of transformation. Two alternative transcripts encoding different isoforms with distinct biological activity have been described. [ 8 ]


Crk together with  CrkL  participates in the  Reelin  signaling cascade downstream of  DAB1 . [ 6 ] [ 7 ]


v-Crk, a transforming oncoprotein from avian sarcoma viruses, is a fusion of viral "gag" protein with the SH2 and SH3 domains of cellular Crk. [ 9 ]  The name Crk is from "CT10 Regulator of Kinase" where CT10 is the avian virus from which was isolated a protein, lacking kinase domains, but capable of stimulating phosphorylation of tyrosines in cells. [ 10 ]


Crk should not be confused with  Src , which also has cellular (c-Src) and viral (v-Src) forms and is involved in some of the same signaling pathways but is a protein tyrosine-kinase.


CRK (gene) has been shown to  interact  with:


ENSG00000006530 ENSG00000262327


NM_018238 NM_001364948


The human  gene   AGK  encodes the  enzyme   mitochondrial acylglycerol kinase . [ 5 ] [ 6 ] [ 7 ] [ 8 ]


The protein encoded by this gene is a  mitochondrial  membrane protein involved in  lipid  and  glycerolipid  metabolism. It catalyzes the formation of  phosphatidic  and  lysophosphatidic acids . Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10.


Diseases associated with AGK include  cataracts  and  cardiomyopathy . An important  paralog  of this gene is  CERKL .


The AGK gene is located on the 7th chromosome, with its specific location being 7q34. The gene contains 18 exons. [ 8 ]  AGK encodes a 47.1 kDa protein that is composed of 422 amino acids; 32 peptides have been observed through mass spectrometry data. [ 9 ] [ 10 ]


Acylglycerol kinase synthesizes  phosphatidic  and  lysophosphatidic  acids. The enzyme uses ATP to put a  phosphate  group on acyl glycerol and diacylglycerol. It catalyzes the following reactions:


ATP + acylglycerol = ADP + acyl-sn-glycerol 3-phosphate.
ATP + 1,2-diacyl-sn-glycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate.


The enzyme is involved in the more general pathway of  fatty acid metabolism . AGK also has an implicated role in the assembly of the  adenine   nucleotide  translocator in the inner mitochondrial membrane.
 [ 11 ]


Mutations in the AGK gene were the first to be implicated in isolated  cataract  development, although it is unclear whether these mutations cause a change in  lipid  composition of the lenses, or if signaling results in the defect. [ 12 ]  This gene has also been associated with  Sengers syndrome . Two different phenotypes have been observed. One form of the disorder presented as  vascular strokes ,  lactic acidosis ,  cardiomyopathy  and cataracts, abnormal muscle cell histopathology and mitochondrial function. In those patients, there was also a markedly high rate of citrate synthase. The second phenotype presented with similar clinical symptoms, but no strokes. As phosphatidic acid is also involved in the synthesis of  phospholipids , its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue. [ 13 ]


AGK expression has also been correlated with certain  cancer  phenotypes. AGK expression, in coordination with AGX, was not detected in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci and capsular invasion. [ 14 ]  Overexpression of AGK sustains constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly increases STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. [ 15 ]  In prostate cancer, AGK expression amplifies EGF signaling pathways, thus playing a significant role in the development of prostate cancer. [ 16 ]  It's also correlated tumor-nodule-metastasis (TNM) classification breast cancer, and an overall shorter overall survival. [ 17 ]


In the progression of diabetic retinopathy, the ATX-AGK-LPA signaling axis plays a significant role. [ 18 ]


In the proliferation of prostate cancer, AGK interacts with and regulates PC-3 prostate cancer cells markedly increased formation and secretion of  LPA . This increase also affects the EGF receptor and sustained activation of extracellular signal related kinase (ERK) 1/2, culminating in enhanced cell proliferation. [ 16 ]  Acylglycerol kinase also augments JAK2/STAT3 signaling in esophageal squamous cells. [ 15 ]


AHDC1 [ 1 ]  is a  gene , changes in which are found through clinical studies to cause an array of symptoms in affected children known collectively as  Xia-Gibbs Syndrome , [ 2 ] [ 3 ]  including global  developmental delay , global  hypotonia , obstructive  sleep apnoea  and  seizures .


In 2014, a  human genetic disorder  (Xia-Gibbs Syndrome) caused by  de novo  mutations  in  AHDC1  was discovered through  whole-exome sequencing . [ 4 ]  Four patients were identified in the paper which recorded the initial discovery and their clinical features were reported,  including global developmental delay, hypotonia, obstructive sleep apnea, intellectual disability and seizures. The publication of the paper and discovery of the new condition was reported in the media including in Science Daily and in Baylor College of Medicine News. [ 5 ] [ 6 ] [ 7 ]  Subsequent research has identified and reported the clinical features of an additional seven patients and there are now known to be twenty confirmed cases. [ 8 ]


2Y7B ,  4XH3 ,  4XOI


NM_001284301 NM_001284302 NM_018685


NP_001271230 NP_001271231 NP_061155


NP_082666 NP_001391862


Anillin  is a conserved protein implicated in cytoskeletal dynamics during cellularization and  cytokinesis . The  ANLN   gene  in humans and the scraps gene in  Drosophila  encode Anillin. [ 5 ]  In 1989, anillin was first isolated in embryos of  Drosophila melanogaster . It was identified as an F-actin binding protein. [ 6 ]  Six years later, the anillin gene was cloned from cDNA originating from a Drosophila ovary. Staining with anti-anillin (Antigen 8)  antibody  showed the anillin localizes to the nucleus during interphase and to the contractile ring during cytokinesis. [ 7 ]  These observations agree with further research that found anillin in high concentrations near the cleavage furrow coinciding with RhoA, a key regulator of contractile ring formation. [ 8 ]


The name of the protein anillin originates from a Spanish word,  anillo .  Anillo  means ring and shows that the name anillin references the observed enrichment of anillins at the contractile ring during cytokinesis. Anillins are also enriched at other actomyosin rings, most significantly, those at the leading edge of the Drosophila embryo during cellularization. These actomyosin rings invaginate to separate all nuclei for one another in the syncytial blastoderm. [ 5 ]


Anillin has a unique multi-domain structure. At the N-terminus, there is an actin- and myosin-binding domain. At the C-terminus, there is a  PH domain . The PH domain is conserved and essential for anillin functionality. [ 8 ]  The human anillin cDNA, located on Chr7, encodes a 1,125–amino acid protein with a predicted molecular mass of 124 kD and a pI of 8.1. The mouse anillin gene is located on Chromosome 9. [ 9 ]


There are also numerous anillin-like protein homologues found outside of metazoans. In  Schizosaccharomyces pombe  (fission yeast), there are Mid1p and Mid2p. These two anillin-like proteins do not have any overlap in their functions. Mid1p has been characterized as a key regulator in cytokinesis, responsible for arranging  contractile ring   assembly and positioning. [ 10 ]  Mid2p acts later in cytokinesis to organize  septins  during septation, or the invagination of inner membranes, outer membranes, and the cell wall that occurs in order to separate daughter cells completely. [ 11 ]   Saccharomyces cerevisiae  (budding yeast) also have two anillin-like proteins, Boi1p and Boi2p. Boi1p and Boi2p localize to the nucleus and contractile ring at the bud neck, respectively. They are essential for cell growth and bud formation. [ 12 ]


Anillins are required for the faithfulness of cytokinesis and its F-actin-, myosin-, and septin-binding domains implicate anillin in actomyosin cytoskeletal organization. In agreement with this belief, anillin-mutant cells have disrupted contractile rings. Additionally, it is hypothesized that anillin couples the actomyosin cytoskeleton to microtubules by binding MgcRacGAP/CYK-4/RacGAP50C. [ 13 ]


Anillins have also been shown to organize the actomyosin cytoskeleton into syncytial structures observed in Drosophila embryos or C. elegans gonads. ANI-1 and ANI-2 (proteins homologous to anillin) are essential for embryonic viability in both organisms. ANI-1 is required for cortical ruffling, pseudocleavage, and all contractile events that occur in embryos prior to mitosis. ANI-1 is also crucial for segregation of polar bodies during meiosis. ANI-2 functions in the maintenance of the structure of the central core of the cytoplasm, the  rachis , during oogenesis. ANI-2 ensures oocytes do not disconnect prematurely from the rachis, thereby leading to the generation of embryos of varying sizes. [ 14 ]


In vitro experiments suggest that anillin drives myosin-independent actin contractility. [ 15 ]


Anillin specifically binds F-actin, rather than G-actin. Binding of F-actin by anillin only occurs during  cell division . Anillin also bundles actin filaments together and drives their relative sliding. [ 15 ]  This contractile behavior is independent of myosin and ATP and may couple with actin filament disassembly. Amino acids 258-340 are sufficient and necessary for F-actin binding in Drosophila, but amino acids 246-371 are necessary to bundle actin filaments. [ 7 ]  The ability of anillin to bind to and bundle actin together is conserved through many species. It is hypothesized that by regulating actin bundling, anillin increases the efficiency of actomyosin contractility during cell division. Both anillin and F-actin are found in contractile structures. They are recruited independently to the contractile ring, but F-actin increases the efficiency of anillin targeting. [ 5 ]  Anillin may also be involved in promoting the polymerization of F-actin by stabilizing formin mDia2 in an active form. [ 16 ]


Anillin interacts directly with non-muscle myosin II and interacts indirectly with myosin via F-actin. Residues 142-254 (near the N-terminus) are essential for anillin binding myosin in  Xenopus . The interaction of anillin and myosin is also dependent on phosphorylation of the myosin light chain. [ 17 ]  The interaction of myosin and anillin does not seem to serve in recruitment, but rather organization of myosin. In  Drosophila , anillin is necessary to organize myosin into rings in the cellularization front. [ 18 ]  Depletion of anillin in  Drosophila  and humans leads to changes in the spatial and temporal stability of myosin during cytokinesis. [ 19 ]  In C. elegans, ANI-1 organizes myosin into foci during cytokinesis and establishment of polarity, whereas, ANI-2 is a requirement for the maintenance of myosin-rich contractile lining of oogenic gonads. [ 14 ]


Septin localization during cytokinesis and cellularization is dependent on its association with anillin. [ 20 ]  The direct interaction between anillin and septins was first shown by the interaction seen between  Xenopus  anillin and a minimal reconstituted heterooligomer of human septins 2, 6, and 7. [ 21 ]  The ability of anillin to bind to septins is dependent on the C-terminal domain, which contains a terminal PH domain and an upstream sequence known as the “Anillin Homology” (AH) domain. [ 9 ]


The AH domain of human anillin is essential for its interaction with  RhoA . Depletion of RhoA halts contractile ring assembly and ingression, whereas, anillin depletion leads to a less severe phenotype when the contractile ring forms and ingresses partially. Depletion of anillin in Drosophila spermatocytes greatly reduces the localization of Rho and F-actin to equatorial regions. [ 19 ]


Anillin interacts with  Ect2 , further supporting the idea that anillin stabilizes RhoA localization since Ect2 is an activator of RhoA. Independent of RhoA, the interaction between anillin and Ect2 occurs. This interaction is essential of the  GEF  activity of Ect2 and requires the AH domain of anillin and the PH domain of Ect2. [ 22 ]


Drosophila  anillin interacts with Cyk-4, a central spindle protein, indicating that anillin may have a role in determining the division plane during cytokinesis. [ 23 ]  In anillin-depleted larval cells, the central spindle does not extend to the cortex. [ 24 ]  Human anillin-depleted cells show improperly positioned and distorted central spindles. [ 25 ]


Anillin was first isolated from  Drosophila  by harnessing its interactions with both F-actin and microtubules. [ 26 ]  Furthermore, anillin-rich structures that form after Latrunculin A treatment of  Drosophila  cells localize to the plus-ends of microtubules. [ 27 ]  The interaction between anillin and microtubules suggest that anillin may serve as a signaling factor to relay the position of the mitotic spindle to the cortex to ensure appropriate contractile ring formation during cytokinesis. [ 5 ]


Anillins in metazoans are heavily phosphorylated; however, the kinases responsible for the phosphorylation are unknown at the present time. In humans and  Drosophila , anillins are recruited to the equatorial cortex in a RhoA-dependent manner. This recruitment is independent of other cytoskeletal Rho targets such as myosin, F-actin, and Rho-kinase. It has been observed that anillin proteolysis is triggered after mitotic exit by the  Anaphase Promoting Complex  (APC).


Most anillins can be sequestered to the nucleus during  interphase , but there are exceptions –  Drosophila  anilins in the early embryo, C. elegans ANI-1 in early embryos,  C. elegans  ANI-2 in oogenic gonads, and Mid2p in fission yeast. These anillins that are not sequestered during interphase suggest that anillins may also regulate cytoskeletal dynamics outside the contractile ring during cytokinesis. [ 6 ]


Anillin is critical for cell division and therefore development and homeostasis in metazoans. In recent years, the expression levels of anillin have been shown to correlate to the metastatic potential of human tumours. In colorectal cancer, expression levels of anillin are higher in tumours and when anillin was over-expressed in HT29 cells, a classical  colorectal cancer  cell line, the cells showed faster replication kinetics due to the lengthening of G2/M phase. Increasing the expression of anillin also led to further invasiveness and migration of numerous colorectal cancer cell lines. The hypothesis from such observations is that anillin promotes EMT and  cell migration  through cytoskeletal remodeling, leading to enhanced proliferation, invasion, and mobility of tumour cells. [ 28 ] [ 29 ]


NM_001175 NM_001321420 NM_001321421 NM_001321422 NM_001321423


NP_001166 NP_001308349 NP_001308350 NP_001308351 NP_001308352


Rho GDP-dissociation inhibitor 2  is a  protein  that in humans is encoded by the  ARHGDIB   gene . [ 5 ] [ 6 ] [ 7 ]  Aliases of this gene include  RhoGDI2 ,  GDID4 ,  Rho GDI 2 , and others. [ 8 ]


ARHGDIB has been shown to  interact  with  VAV1 [ 9 ]  and  Src . [ 10 ]


RhoGDI2 (ARHGDIB) is part of a family of three members:  RhoGDI1 , RhoGDI2 (also known as RhoGDIB, D4-GDI or Ly-GDI) and  RhoGDI3 .  RhoGDI1 is expressed in many organs and is the best studied member of the family. [ 11 ] [ 12 ] [ 13 ]  RhoGDI2 was initially believed to be expressed specifically in blood forming cells, [ 6 ]  but has subsequently been found to be highly expressed in a variety of other cell types as well. [ 14 ]  RhoGDI3 is predominantly expressed in brain, lung, kidney, testis and pancreas, [ 15 ] [ 16 ]  and is targeted to specific parts of the cell such as the Golgi where it may play a role in transport or proteins in cells. [ 17 ] [ 18 ]


Despite a high degree of sequence similarity, RhoGDI1 and RhoGDI2 are very different in their binding affinities for specific  GTPases , [ 19 ]  and more importantly, in their roles in tumor formation and spread of tumor to other organs (the process of  metastasis ). [ 20 ]   For example, RhoGDI2 functions as a suppressor of metastasis but not a  tumor suppressor  in  bladder cancer  cells, [ 14 ] [ 21 ]  while RhoGDI1 is a ubiquitous suppressor of tumor growth in all sites so far examined in bladder cancer models), [ 22 ]  suggesting that their cellular functions must diverge to cause these differential effects.


While there are clear links between the alteration of RhoGDI2 protein levels and disease progression and/or metastasis in several types of cancer, the mechanistic underpinnings of the mode of RhoGDI2 action under carcinogenic cellular conditions are only now beginning to be understood.  Evidence demonstrates that RhoGDI2 inhibits the  endothelin  axis and crosstalk with  macrophages  within the  micrometastatic  microenvironment to inhibit metastatic outgrowth. [ 23 ]  As such, RhoGDI2 could prove important in the regulation of tumor dormancy. Targeting this axis with orally available endothelin receptor antagonists [ 24 ]  may prove efficacious in mimicking the inhibitory role of RhoGDI2 by preventing macrophage infiltration into the micrometastatic niche. [ 25 ]  Recent work has also determined that genetic and pharmacologic targeting of chemokine (C-C motif) ligand 2 ( CCL2 ) also known as monocyte chemotactic protein-1 (MCP-1) or small inducible cytokine A2, its receptor  CCR2  and pharmacologic ablation of macrophages can also phenocopy the effect of RhoGDI2 expression to prevent metastatic colonization of the lung67 and that RhoGDI2 is suppressor of  versican , a protein that has been shown to promote cell migration [ 26 ]  and metastasis in several tumor models.


In contrast to its role as a metastasis suppressor in bladder cancer, in breast, RhoGDI2 expression has been reported to be upregulated in cancer [ 27 ]  and to promote invasion of breast cancer cells, [ 28 ]  while another report found a biphasic expression pattern of RhoGDI2 in breast cancer with decreased expression correlating with lymph node metastasis. [ 29 ]


ARHGDIB antibodies may be a marker for long-term kidney graft loss in recipients of deceased-donor kidneys. [ 30 ]


NM_199004 NM_001330064


NM_001271358 NM_001271359 NM_001271360 NM_145429


NP_004304 NP_945355


NP_001258287 NP_001258288 NP_001258289 NP_663404


Beta-arrestin-2 , or  β-arrestin2 , also known as  arrestin beta-2 , is an intracellular  protein  that in humans is encoded by the  ARRB2   gene .


Members of  arrestin /beta-arrestin protein family are thought to participate in agonist-mediated desensitization of  G protein-coupled receptors  and cause specific dampening of cellular responses to stimuli such as hormones, neurotransmitters, or sensory signals, [ 5 ] [ 6 ] [ 7 ]  as well as having signalling roles in their own right. [ 8 ] [ 9 ] [ 10 ] [ 11 ] [ 12 ]  Arrestin beta 2, like  arrestin beta 1 , was shown to inhibit  beta-adrenergic receptor  function in vitro. It is expressed at high levels in the central nervous system and may play a role in the regulation of synaptic receptors. Besides the brain, a  cDNA  for arrestin beta 2 was isolated from  thyroid gland , and thus it may also be involved in hormone-specific desensitization of  TSH receptors . Multiple  alternatively spliced  transcript variants have been found for this gene, but the full-length nature of some variants has not been defined. [ 13 ]


The protein may interact with the agonist  DOI  in  5-HT 2A  receptor  signaling. [ 14 ] [ 15 ]


Arrestin beta 2 is crucial for the development of  tolerance  to  morphine  and other  opioids .


Arrestin beta 2 has been shown to  interact  with


This article incorporates text from the  United States National Library of Medicine , which is in the  public domain .


3MQM ,  3OPE ,  4YNM ,  4YNP ,  4YPA ,  4YPE ,  4YPU


NM_018489 NM_001366177


NP_060959 NP_001353106


ASH1L  (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a  histone-lysine N-methyltransferase  enzyme encoded by the  ASH1L  gene located at chromosomal band 1q22.  ASH1L is the human homolog of Drosophila Ash1 (absent, small, or homeotic-like).


Ash1 was discovered as a gene causing an imaginal disc mutant phenotype in Drosophila.  Ash1 is a member of the  trithorax-group  (trxG) of proteins, a group of transcriptional activators that are involved in regulating  Hox gene  expression and body segment identity. [ 5 ]   Drosophila Ash1 interacts with trithorax to regulate  ultrabithorax  expression. [ 6 ]


The human ASH1L gene spans 227.5 kb on chromosome 1, band q22.  This region is rearranged in a variety of human cancers such as leukemia, non-Hodgkin's lymphoma, and some solid tumors.  The gene is expressed in multiple tissues, with highest levels in brain, kidney, and heart, as a 10.5-kb mRNA transcript. [ 7 ]  Mutations in ASH1L in humans have been associated with autism, epilepsy, and intellectual disability. [ 8 ]


Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa. [ 9 ]   ASH1L has an  associated with SET  domain (AWS), a  SET domain , a post-set domain, a  bromodomain , a  bromo-adjacent homology domain , and a plant homeodomain finger ( PHD finger ).  Human and Drosophila Ash1 share 66% and 77% similarity in their SET and PHD finger domains, respectively. [ 7 ]   A bromodomain is not present in Drosophila Ash1.


The  SET domain  is responsible for ASH1L's  histone methyltransferase  (HMTase) activity.  Unlike other proteins that contain a SET domain at their C terminus, ASH1L has a SET domain in the middle of the protein.  The  crystal structure  of the human ASH1L catalytic domain, including the AWS, SET, and post-SET domains, has been solved to 2.9 angstrom resolution.  The structure shows that the substrate binding pocket is blocked by a loop from the post-SET domain, and because mutation of the loop stimulates ASH1L HMTase activity, it was proposed that this loop serves a regulatory role. [ 10 ]


ASH1L is ubiquitously expressed throughout the body. [ 11 ] [ 12 ] [ 13 ] [ 14 ]  In the brain, ASH1L is expressed across brain areas and cell types, including excitatory and inhibitory neurons, astrocytes, oligodendrocytes, and microglia. [ 15 ] [ 16 ] [ 17 ]  ASH1L also does not appear to show specificity to any brain region. In humans, ASH1L mRNA expression levels are fairly equal across all regions of cortex. [ 18 ] [ 19 ]  Similarly, in mice, ASH1L protein is highly expressed in the hippocampus, thalamus, hypothalamus, motor cortex, and basolateral amygdala. [ 20 ]  In humans, ASH1L expression peaks prenatally and decreases after birth, with a second peak in expression towards adulthood. [ 18 ] [ 19 ]   In mouse, ASH1L is expressed in the developing central nervous system as early as embryonic day 8.5  [ 21 ] [ 13 ]  and is still expressed throughout the adult mouse brain. [ 22 ]  Overall, the expression of ASH1L in the brain is spatially and temporally broad.


The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling. [ 7 ]   ChIP analysis demonstrated that ASH1L binds to the 5'-transcribed region of actively transcribed genes.  The chromatin occupancy of ASH1L mirrors that of the TrxG-related H3K4-HMTase MLL1; however, ASH1L's association with chromatin can occur independently of  MLL1 .  While ASH1L binds to the 5'-transcribed region of housekeeping genes, it is distributed across the entire transcribed region of  Hox genes .  ASH1L is required for maximal expression and H3K4 methylation of HOXA6 and HOXA10. [ 23 ]


A Hox promoter reporter construct in HeLa cells requires both MLL1 and ASH1L for activation, whereas MLL1 or ASH1L alone are not sufficient to activate transcription. The methyltransferase activity of ASH1L is not required for Hox gene activation but instead has repressive action.  Knockdown of ASH1L in K562 cells causes up-regulation of the ε-globin gene and down-regulation of myelomonocytic markers GPIIb and GPIIIa, and knockdown of ASH1L in lineage marker-negative hematopoietic progenitor cells skews differentiation from myelomonocytic towards lymphoid or erythroid lineages.  These results imply that ASH1L, like MLL1, facilitates myelomonocytic differentiation of hematopoietic stem cells. [ 5 ]


The in vivo target for ASH1L's HMTase activity has been a topic of some controversy.  Blobel's group found that in vitro ASH1L methylates H3K4 peptides, and the distribution of ASH1L across transcribed genes resembles that of H3K4 levels. [ 23 ]   In contrast, two other groups have found that ASH1L's HMTase activity is directed toward H3K36, using nucleosomes as substrate. [ 10 ] [ 24 ]


There are over 100 reported pathogenic, or disease-causing, variants in the ASH1L gene. [ 25 ] [ 26 ] [ 27 ] [ 28 ] [ 29 ] [ 30 ] [ 31 ] [ 32 ] [ 33 ] [ 34 ] [ 35 ] [ 36 ] [ 37 ] [ 38 ] [ 39 ] [ 40 ] [ 41 ] [ 42 ] [ 43 ] [ 44 ] [ 45 ] [ 46 ] [ 47 ]  About half of the variants arise de novo, and half are inherited. Of the inherited variants, about half are maternally inherited and half are paternally inherited. Disease-causing variants may be missense, nonsense, or frameshift mutations. The missense mutations are distributed throughout the gene body without localizing to a known functional domain of ASH1L.


All affected humans are heterozygous for ASH1L mutations. A single pathogenic copy of ASH1L causes disease, which may be the result of two different genetic mechanisms: haploinsufficiency or dominant negative function. The ClinGen clinical genomics resource states that there is “Sufficient Evidence for Haploinsufficiency” in ASH1L. [ 48 ]


The most common phenotypes, or symptoms, related to ASH1L mutations are  autism spectrum disorder  (ASD),  epilepsy ,  intellectual disability , and  attention deficit hyperactivity disorder  (ADHD). The Simons Foundation Autism Research Initiative (SFARI) gives ASH1L a score of 1.1, indicating that ASH1L is a high confidence autism gene with the best level of evidence linking it to autism. [ 8 ]


The term  Athanogene , derived from the Greek for "against death" (' athánatos ), was incorporated into name of the gene Bcl-2-associated athanogene 1 ( BAG-1 ; alias HAP46/BAG-1M) upon discovery of its ability to confer transfected cells with resistance to apoptosis. [ 1 ] [ 2 ]


NM_001688 NM_001002014 NM_001002015


NM_009725 NM_001304719


NP_001291648 NP_033855


ATP synthase subunit b, mitochondrial  is an  enzyme  that in humans is encoded by the  ATP5PB   gene . [ 5 ] [ 6 ]


This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the b subunit of the proton channel. [ 6 ]


The b subunits are part of the peripheral stalk that links the F1 and FO complexes together, and which acts as a stator to prevent certain subunits from rotating with the central rotary element. The peripheral stalk differs in subunit composition between mitochondrial, chloroplast and bacterial F-ATPases. In bacterial and chloroplast F-ATPases, the peripheral stalk is composed of one copy of the delta subunit (homologous to OSCP in mitochondria), and two copies of subunit b in bacteria, or one copy each of subunits b and b' in chloroplasts and  photosynthetic   bacteria . [ 7 ]


Auxiliary metabolic genes  (AMGs) are found in many  bacteriophages  but originated in  bacterial  cells. [ 1 ]  AMGs modulate host cell  metabolism  during infection so that the phage can replicate more efficiently. For instance, bacteriophages that infect the abundant marine  cyanobacteria   Synechococcus  and  Prochlorococcus  ( cyanophages ) carry AMGs that have been acquired from their immediate host as well as more distantly-related bacteria. [ 2 ]  Cyanophage AMGs support a variety of functions including  photosynthesis , [ 3 ]   carbon metabolism , [ 4 ]   nucleic acid  synthesis and metabolism. [ 5 ]  AMGs also have broader ecological impacts beyond their host including their influence on biogeochemical cycling. [ 6 ]


AMGs employ diverse functions including pathways not involved in metabolism despite what the name suggests. They are categorized in two classes based on their presence in the  Kyoto Encyclopedia of Genes and Genomes  (KEGG). [ 7 ]  AMGs do not encompass metabolic genes involved in typical viral functions, such as nucleotide and protein metabolism since their functions achieve direct viral reproduction, rather than augmenting host function to indirectly enhance it. [ 8 ]


Class I AMGs encode for metabolism pathways in the cell and are found in  KEGG . In particular, these genes are found in photosynthesis and carbon metabolism.  psbA  is almost a ubiquitous photosynthetic AMG for the photosystem Il reaction center D1 found in  Synechococcus  and  Prochlorococcus   cyanophages . [ 9 ]  Photosynthetic machinery for other reaction centers and electron transport are also found in many viruses infecting phototrophs. Phages encode for nearly all genes involved in carbon metabolism. [ 7 ]  In particular, viruses redirect host metabolism to increase dNTP biosynthesis for viral genome replication. [ 10 ]   glgA  can induce starvation by converting glucose-6-phosphate to glycogen, forcing the host to compensate by deriving ribulose-5-phosphate from glyceraldehyde-3-phosphate and fructose-6-phosphate. [ 7 ]


Class II AMGs encode for peripheral functions absent from the  KEGG  metabolic pathways. This includes genes typically involved in transport and assembly. [ 8 ]  Major representatives of this class are involved in balancing TCA cycle intermediates. [ 7 ]  Additionally, the acquisition of biogenic elements outside of carbon like phosphate, governed by  pstS , are prevalent for this class. [ 11 ]  Confidence of AMG identification for Class II AMGs is reduced without a database for reference. [ 12 ]


Virus survival through inclusion of AMGs is governed by the laws of natural selection and has been made highly selective through co-evolution with their hosts. [ 13 ]  As such, the AMGs that confer a fitness advantage to the virus's ability to infect a host and reproduce will be more abundant. AMG abundance is largely dictated by the lifestyle of the virus, environmental conditions surrounding it, and host characteristics. [ 6 ]


Lytic  and  lysogenic  viruses have different lifestyles which impact what AMGs they acquire.  Lytic  viruses tend to use AMGs to repurpose host cell metabolism and steal nutrients when in high cell density. Therefore, AMGs related to  metabolism  and transport are found more abundantly in  lytic  viruses. [ 14 ]   Lytic  viruses also encompass a more diverse set of AMGs than  lysogenic  viruses, in part due to their larger host range and higher infection frequency.  Temperate  viruses, on the other hand, may employ AMGs to improve host fitness and virulence due to their often longer lifespan in the cell as a  prophage . [ 15 ]  Gene density in these viruses is higher when compared to their  lytic  counterparts. Higher rates of HGT in  lysogenic  viruses allows for more AMG transfer but also lowers overall gene diversity. [ 6 ]


Photosynthesis  capacity has also been correlated to AMG diversity. Aphotic viral communities possess greater AMG diversity than those in the photic zone. [ 16 ]


Pathways utilizing nutrients found in low concentrations in the local environment are generally found in higher abundance in the virus. In  marine  environments, AMGs can confer fitness advantages for both host and viruses under relatively nutrient-limited conditions compared to sediment and strong ultraviolet stress of water. [ 6 ]  In sunlit versus dark ocean waters, AMGs in distinct pathways are unequally distributed to reprogram host energy production and viral replication based on available nutrients. [ 17 ]  In sedimentary environments, carbon and sulfur metabolism AMGs are typically more prevalent to outcompete other organisms for the abundant resources. [ 18 ]


A virus's host range determines which host it can acquire AMGs from. Additionally, the abundance of a host surrounding a virus will affect its likelihood to acquire genes from the host. Virus populations increasingly occupy lytic lifestyles as bacterial production increases. [ 14 ]  The strong evolutionary connection between viruses and their hosts makes AMG acquisition mirror the host's own adaptation to its environment over time. [ 6 ]


Synechococcus  and  Prochlorococcus  are the most abundant  picocyanobacteria , accounting for up to 50% of primary production in the marine environment. [ 19 ]  As such, many AMGs characterized have been discovered in  phages  of these host systems.


DRAM-v [ 20 ]  is the standard for AMG annotation of metagenome assembled genomes (MAGs) identified as  viruses . [ 21 ]  DRAM-v searches the following databases for AMGs that match the input MAGs:  Pfam ,  KEGG ,  UniProt ,  CAZy ,  MEROPS , VOGDB, and  NCBI  Viral RefSeq. [ 20 ]   KEGG  can then be referenced to classify annotated AMGs through VIBRANT. [ 22 ]


Since AMGs originate in hosts, distinguishing host and viral genes is critical for their study. This is not easily achieved as cultivation of viral-host systems in a laboratory setting proves challenging if even possible. [ 8 ]  Additionally, filtering out cellular sequences before entry in bioinformatic pipelines is not possible with cellular  gene transfer agents  and  membrane vesicles  are unable to distinguish from  viruses  due to their many shared properties at this step of analysis. [ 23 ] [ 24 ]  The extent to which they have contaminated existing viral databases is unknown. [ 8 ]  Some genes have distinctions between host and viral versions such as  cyanophage   photosynthesis  easing the task of computational distinction. The most definitive way developed to determine gene origin has been identification of taxonomically informative genes colocalized on assembled  contigs . ViromeQC [ 25 ]  can display contamination for the dataset overall and DRAM-v assigns a confidence score for the AMG being on a viral MAG. [ 20 ]  Viral identification is most popularly performed by VIBRANT, [ 22 ]  VirSorter2, [ 26 ]  DeepVirFinder, [ 27 ]  and CheckV. [ 28 ]


AMGs are not randomly distributed throughout  genomes . Current research is being done to determine the  genes  that most commonly surround specific AMGs. [ 29 ]  Hyperplastic regions including the region between  genes  g15-g18 has been classified as locales where multiple AMGs have been inserted. [ 30 ]  Possible AMG contexts can be divided into locally collinear blocks (LCBs), or homologous regions shared by multiple  viruses  without rearrangements. [ 31 ]  AMGs have been found in just one or up to 14 LCBs. Those found in more diverse contexts have also shown up in variable locales within the LCB. [ 29 ]


Horizontal gene transfer  (HGT) from host to virus allows for AMGs to be acquired. Gene transfer from host  eukaryotes  to  viruses  occur about twice as frequently as virus to host gene transfers due to a higher number viral recipients than donors. The vast majority of gene transfer occurs in double-stranded  DNA viruses  since they have large and flexible  genomes , co-evolution with  eukaryotes , and wide host breadth. Additionally, unicellular hosts more commonly transfer genes. [ 13 ]


AMGs may influence  gene expression  by modulating the activity of  transcription factors , which control the rate at which specific genes are transcribed into mRNA, thereby impacting the levels of corresponding  proteins  involved in  metabolic pathways .


Certain AMGs encode  proteins  that directly interact with  enzymes  involved in  metabolic  reactions. This interaction can either enhance or inhibit  enzyme  activity, leading to changes in the rate of metabolic flux through specific pathways.


AMGs may be integrated into  cellular signaling  pathways, influencing the transmission of signals related to energy status, nutrient availability, or stress. By modulating these signaling pathways, AMGs can indirectly regulate  metabolic processes .


AMGs have a large impact on  biogeochemical cycles  in multiple environments through nutrient degradation,  mineralization , transportation,  assimilation , and transformation. [ 6 ]  By enhancing the metabolic capabilities of their hosts, bacteriophages contribute to the recycling of organic matter, influencing the availability of nutrients for other organisms in the ecosystem. Lytic viruses in particular have been shown to increase ammonium oxidation, nitric oxide reduction, nitrification, and denitrification to balance nutrient levels in nitrogen polluted environments. [ 6 ]  Nutrient-enriched wetlands contain AMGs related to sulfur transport and metabolism. [ 32 ]  AMG modification of host processes is another means other than the viral shunt by which viruses can directly impact biogeochemical cycles. [ 33 ]


The ability of AMGs modulating the  metabolic  capacities of their hosts can influence the abundance and distribution of specific microbial taxa. [ 6 ]  In turn, this shapes the overall composition of microbial communities, with potential cascading effects on higher  trophic levels . [ citation needed ]


AMGs play a crucial role in microbial adaptation to environmental changes. In extreme environments, AMGs can encode for alternate energy pathways such as subunits of  dissimilatory sulfite reductase . [ 34 ]  The ability of viruses to confer new metabolic traits to their hosts enhances the resilience of microbial communities facing shifts in temperature, nutrient availability, or other environmental stressors. [ 6 ]  AMGs can also serve as a genetic pool in shaping the evolution of their hosts. [ 35 ]


Beta-1,3-N-acetylgalactosaminyltransferase 2  is a  protein  that in humans is encoded by the B3GALNT2  gene .
 [ 1 ]


This gene encodes a member of the glycosyltransferase 31 family. The encoded protein synthesizes GalNAc:beta-1,3GlcNAc, a novel  carbohydrate  structure, on  N-  and  O-glycans . Alternatively spliced  transcript variants  that encode different  isoforms  have been described. [provided by RefSeq, Mar 2013].


A mutation in B3GALNT2 is known to cause dystroglycanopathy congenital with brain and eye anomalies A11 (MDDGA11), which is an autosomal recessive muscular dystrophy. [ 2 ]


This article on a  gene  on human  chromosome 1  is a  stub . You can help Wikipedia by  expanding it .


NM_001270731 NM_001270732 NM_001270733 NM_001270734 NM_001270735 NM_015367 NM_001363824


NP_001257660 NP_001257661 NP_001257662 NP_001257663 NP_001257664 NP_056182 NP_001350753


BCL2-like 13 (apoptosis facilitator) , also known as  BCL2L13  or  Bcl-rambo , is a  protein  which in humans is encoded by the  BCL2L13   gene  on chromosome 22. This gene encodes a  mitochondrially -localized protein which is classified under the Bcl-2 protein family. Overexpression of the encoded protein results in  apoptosis . [ 5 ] [ 6 ]  As a result, it has been implicated in cancers such as childhood  acute lymphoblastic leukemia  (ALL) and  glioblastoma multiforme  (GBM). [ 7 ] [ 8 ]  Alternatively spliced transcript variants have been observed for this gene, such as Bcl-rambo beta. [ 5 ] [ 9 ]


As a member of the Bcl-2 protein family, Bcl-rambo comprises four conserved  BH domains  and a transmembrane (TM) domain. However, unlike the other members, Bcl-rambo does not require the BH domains for its apoptotic function, relying instead on the mitochondrial localization carried out by the TM domain. In addition to these domains, it has conserved B-cell lymphoma 2 homology motifs, as well as an extension at its c-terminal, termed the BHNo domain, which contains two  tandem repeats , RTA and RTB. [ 5 ] [ 9 ]


An alternatively-spliced protein variant, called Bcl-rambo beta, is composed of only the BH4 domain, completely lacking the BH domains 1 through 3 due to an in-frame  stop codon  inserted by an  Alu element . Without the TM domain, this variant remains in the  cytosol  and does not localize to the mitochondria. Nonetheless, it still performs proapoptotic activity, mediated by the encoded Alu element, though the exact mechanisms remain to be elucidated. [ 10 ]


Bcl-rambo is a member of the  Bcl-2  family of proteins that regulate  apoptosis . In cells, Bcl-rambo is localized to the  mitochondria , and its overexpression induces apoptosis that is blocked by  caspase  inhibitors, whereas inhibitors controlling upstream events of either the 'death receptor' ( FLIP ,  FADD-DN ) or the 'mitochondrial' pro-apoptotic pathway ( Bcl-x(L) ) had no effect. [ 6 ]  Bcl-rambo mediates apoptosis by associating with  adenine nucleotide translocator  (ANT), a component of the mitochondrial permeability transition pore, to induce its opening. ANT will also facilitate the transfer of ADP and ATP between the cytosol and the matrix. [ 9 ]


The BCL2L13 gene has been implicated in a wide spectrum of cancers. Previous clinical studies observed in ALL patients that high expression of  BCL2L13  correlated to lower event-free and overall survival. Though statistically significant, the observations contradict the accepted pro-apoptotic function of  BCL2L13 ’s gene product, which should have contributed to cancer cell death and, thus, more favorable survival outcomes. Two possible explanations propose that either 1) Bcl-rambo performs a different biological role in childhood, or 2) alternative splicing could have generated an anti-apoptotic variant. More research is necessary to resolve this discrepancy. [ 7 ]  In another type of cancer, GBM, Bcl-rambo is known to inhibit induced apoptosis in GBM cells by binding two other pro-apoptotic proteins, ceramide synthases 2 (CerS2) and 6 ( CerS6 ), thereby blocking CerS2/6 complex formation and activity. Thus, inhibiting  BCL2L13  during cancer treatments may improve survival outcomes. [ 8 ]


BCL2L13 has been shown to  interact  with:


2P1L ,  2PON ,  3DVU ,  4DDP ,  4MI8


NM_001313998 NM_001313999 NM_001314000 NM_003766


NM_019584 NM_001359819 NM_001359820 NM_001359821


NP_001300927 NP_001300928 NP_001300929 NP_003757


NP_062530 NP_001346748 NP_001346749 NP_001346750


Beclin-1  is a  protein  that in humans is encoded by the  BECN1   gene . [ 5 ] [ 6 ]  Beclin-1 is a mammalian   ortholog  of the yeast autophagy-related gene 6 (Atg6)  and BEC-1 in the  C. elegans   nematode . [ 7 ]  This protein interacts with either  BCL-2  or  PI3k  class III, playing a critical role in the regulation of both  autophagy  and  cell death .


Beclin-1 plays an important role in  tumorigenesis , and  neurodegeneration , being implicated in the  autophagic   programmed cell death . [ 8 ]   Ovarian cancer  with upregulated  autophagy  has a less aggressive behavior and is more responsive to chemotherapy. [ 9 ]


Schizophrenia  is associated with low levels of Beclin-1 in the hippocampus of those affected, which causes diminished  autophagy  which in turn results in increased neuronal cell death. [ 10 ]


BECN1 has been shown to  interact  with:


Beta-1,3-N-acetylglucosaminyltransferase radical fringe , also known as  radical fringe  is a  protein  that in humans is encoded by the  RFNG  gene. Radical fringe is a signaling  enzyme  involved in the arrangement of the embryonic limb buds. It is a member of the  fringe gene  family, which also includes  manic fringe  and  lunatic fringe . It is important for the dorsoventrally patterning of the limb and has been implicated in the formation of the  apical ectodermal ridge  (AER). The AER is essential for the distal patterning of the limb. Experiments executed in chicken models show Radical fringe is expressed in both the dorsal ectoderm and the AER. This provides evidence that the AER forms from cells already expressing radical fringe, though further evidence is needed to confirm. Grafting experiments have shown that formation of the AER comes from signals in the limb bud  mesoderm . However, radical fringe acts as a permissive signal to create a boundary for the AER to form. The knockout experiments done in chicken models suggest Radical fringe plays an integral role in wing development.


Conversely, knockout experiments in mice have shown that if Radical fringe is absent no phenotypic differences occur. Further study revealed the absence of mutation is most likely due to redundancy of Manic and Lunatic fringe, which likely take over in the absence of Radical fringe. Radical, Manic, and lunatic  fringe genes  make up a group of enzymes known as 3-beta-N-acetylglucosaminyltransferases. They elongate O-linked fucose residues on notch receptors, which effects neurogenesis through the  notch  signaling pathway. While Radical fringe may not be vital for limb formation in all species, current research suggests it plays an integral role in establishing the pattern of the developing limb when expressed.


Bok (Bcl-2 related ovarian killer)  is a protein-coding gene of the  Bcl-2 family  that is found in many invertebrates and vertebrates. It induces  apoptosis , a special type of cell death. Currently, the precise function of Bok in this process is unknown.


In 1997, the protein Bcl-2-related ovarian killer (Bok) was identified in a yeast  two-hybrid experiment  with a rat ovarian cDNA library in a screen for proteins interacting with Mcl-1, an abundant anti-apoptotic protein. [ 5 ]  The overexpression of Bok induces  apoptosis . Because of its high sequence similarity to  Bak  and  Bax , [ 6 ]  Bok is classified as a member of the Bcl-2 protein family. [ 7 ]
The mouse homologue of Bok is called Matador (Mtd). This name is derived from the Latin term mactator which means butcher or killer. [ 8 ]  Additionally, homologous proteins were found in  Drosophila melanogaster  (fruit fly) and  Gallus gallus  (chicken). [ 9 ]


The human BOK  promoter  is activated by the overexpression of members of the  E2F  hand transcription factor family. Typically, these transcription factors are involved in the promotion of S-phase, so there might be a connection between Bok expression and  cell cycle  progression. [ 10 ]  Due to this regulation of Bok expression by the cell cycle, it was proposed that Bok sensitizes growing cells to stress-induced apoptosis. [ 10 ]


Bok mRNA comprises five exons which code for a 213 amino acid protein, [ 7 ]  called Bok-L. This protein consists of four Bcl-2 homology domains (abbreviated BH1, BH2, BH3, BH4, respectively) and a C-terminal transmembrane region  [ 7 ]  (Figure 1). Its BH3 domain contains a stretch with many leucine residues. This is unique among the Bcl-2 family members. The leucine-rich stretch functions as a nuclear export signal. [ 11 ]  It is recognized by the nuclear exportin Crm1. Mutations in the leucine-rich stretch impair the binding of Crm1 to Bok. [ 11 ]  Consequently, Bok accumulates in the nucleus and triggers apoptosis. [ 11 ]


Due to  alternative splicing ,  Bok  mRNA gives rise to different Bok proteins: Figure 1 illustrates the different splice variants schematically. Full length Bok is named Bok-L.


The shorter version, Bok-S, lacks exon 3. This results in a fusion of the BH3 domain with the BH1 domain. [ 6 ] [ 12 ]  The BH3 domain is involved in the interaction of Bok with Mcl-1 and other molecules. It is dispensable for the induction of apoptosis. [ 12 ]  Expression of Bok-S may be an immediate response to stress signals. It has been shown to induce apoptosis regardless of the presence of anti-apoptotic molecules. [ 6 ]


Another splice variant termed Bok-P was found in  placental  tissue from patients with pre-eclampsia. While Bok-S misses exon 3, Bok-P lacks exon 2. This deletion includes the BH4 domain and parts of the BH3 domain. Bok-P may be the cause for trophoblast cell death in  pre-eclampsia , [ 7 ]  a dangerous pregnancy complication. In pre-eclampsia, typical alterations occur in the maternal kidney and lead to hypertension and proteins in the urine. To date, the cause of this medical condition as well as an appropriate treatment have not been discovered.


The  Bok  gene is activated and produces protein in different tissues. In mice, elevated Bok levels were detected in the  ovary , the  testis , and the  uterus . [ 5 ]  Nevertheless, it also exists in the  brain  and at low levels in most other tissues. [ 13 ]  However, the expression pattern of the Bok gene varies among species.


In humans, Bok is found in a wide range of tissues. The gene is expressed in the  colon , the  stomach , the  testes , the  placenta , the  pancreas , the  ovaries , and the  uterus . [ 14 ]  Furthermore,  more Bok is expressed in fetal tissue compared to adult tissue. Thus, Bok may influence  development .


The subcellular localization of Bok protein is controversial. In  proliferating cells , Bok is found in the  nucleus . [ 15 ]  Upon induction of apoptosis, it was found to tightly associate with  mitochondrial membranes . [ 14 ] [ 15 ]  On the other hand, another group found Bok shuttling between the  cytoplasm  and the nucleus. In their experiments, increased nuclear (not mitochondrial) localization correlated with a stronger apoptotic activity. [ 11 ]


It was found that the cellular ratio of pro-apoptotic to anti-apoptotic Bcl-2 family members effects late  apoptotic events  such as release of  cytochrome c  from the mitochondria and the activation of caspases. Higher levels of pro-apoptotic proteins compared to anti-apoptotic proteins seem to cause apoptosis. In a current model, the formation of  heterodimers  between pro-apoptotic and anti-apoptotic proteins prevents induction of apoptosis. [ 12 ]


The binding of Bok to its interacting partners seems to be mediated by its BH3 domain. [ 7 ]  The splice variant Bok-S lacks this domain and is unable to form heterodimers with other proteins of the Bcl-2 family.


In yeast two-hybrid experiments, Bok was found to interact with the anti-apoptotic proteins Mcl-1, BHRF-1, and Bfl-1. However, interactions with other anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Bcl-w were not detectable  (1). Later studies aimed at confirming an interaction between Bok and pro-apoptotic  Bak  or  Bax  but were not successful. [ 8 ]


Accordingly, coexpression of anti-apoptotic proteins such as Mcl-1 suppresses apoptosis induced by Bok overexpression. [ 5 ]  Consistent with the results mentioned above, coexpression of anti-apoptotic Bcl-2 does not prevent Bok-induced apoptosis. [ 5 ]


Since its discovery in 1997, several attempts have been made to characterize Bok. Due to the increased expression levels in fetal tissue, scientists anticipated a  developmental  role for Bok. Recently, the Bok  knock-out mouse  was created. This mouse shows, however, no developmental defects and normal fertility. [ 13 ]  This finding indicates that the function of Bok seems to overlap with the function of the related pro-apoptotic proteins  Bak  and  Bax .


Several other roles were proposed for Bok, especially in developing cells. [ 12 ] [ 16 ] [ 17 ] [ 18 ]  Since the action of Bok in triggering apoptosis seems to be redundant, it is difficult to assign a specific role to Bok in the presence of Bak and Bax. The study of cells deficient in Bak and Bok or deficient in Bax and Bok, respectively, could help to better characterize the role of Bok in apoptosis. If Bok exerts a critical function, it is likely that this function is limited to certain circumstances, e.g. specific cell types, stress conditions. Thus, these aspects should be assessed in more detail to analyze the physiological and pathological role of Bok.


4KEG ,  4KGH ,  4KGO ,  4N4X ,  5I7K ,  5I7J ,  5I7L


NM_001243193 NM_016583 NM_130852


NP_001230122 NP_057667 NP_570913


BPI fold containing family A, member 1  (BPIFA1), also known as  Palate, lung, and nasal epithelium clone  (PLUNC), [ 5 ]  is a  protein  that in humans is encoded by the  BPIFA1  gene. [ 6 ] [ 7 ]  It was also formerly known as "Secretory protein in upper respiratory tracts" (SPURT). The  BPIFA1  gene sequence predicts 4  transcripts  ( splice variants ); 3 mRNA variants have been well characterized. The resulting BPIFA1 is a secreted protein, expressed at very high levels in  mucosa  of the airways (olfactory and respiratory and  epithelium ) and salivary glands; at high levels in oropharyneal epithelium, including tongue and tonsils; and at moderate levels many other tissue types and glands including pituitary, testis, lung, bladder, blood, prostate, pancreas, levels in the digestive tract (tongue, stomach, intestinal epithelium) and pancreas. [ 8 ]  The protein can be detected on the apical side of epithelial cells and in airway surface liquid, nasal mucus, and sputum. [ 9 ]


BPIFA1 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 10 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 11 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant  homologs  in non-vertebrate species such as insects, mollusks, and roundworms. [ 12 ] [ 13 ]  Within that broad grouping is the BPIF gene family whose members encode the BPI fold  structural motif  and are found clustered on a single chromosome, e.g.,  Chromosome 20  in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes  BPIFA1 ,  BPIFA2 ,  BPIFA3 , and 1 pseudogene  BPIFA4P ; while BPIFB consists of 5 protein encoding genes  BPIFB1 ,  BPIFB2 ,  BPIFB3 ,  BPIFB4 ,  BPIFB6  and 2 pseudogenes  BPIFB5P ,  BPIFB9P . What appears as pseudogenes in humans may appear as fully functional genes in other species.


In humans, the  BPIFA1  gene was first identified as an ortholog of the mouse  Plunc  gene [ 7 ]  which had earlier been identified from a  differential display  screen of the embryonic mouse  palate . [ 14 ]  Subsequently, using  microarray analysis techniques  of human epithelial tissues, the  SPURT  gene and, separately, the  SPLUNC1  gene were identified. [ 15 ] [ 16 ]  These were all recognized to be, in fact, the same gene within the BPI/LBP/PLUNC family.


BPIFA1 has multiple functions but perhaps its most prominent ones are related to BPIFA1's localization in nasal, olfactory, oral, and respiratory epithelium and the mucous/fluids that coat them. BPIFA1/SPLUNC1 binds with high affinity and specificity to  dipalmitoylphosphatidylcholine , one of the major and most important surfactant phospholipids in the airway and lungs. [ 17 ]  By lowering the surface tension in mucosal fluids, BPIFA1/SPLUNC1 inhibits bacteria like  Klebsiella  from proliferating as a biofilm on epithelium. [ 18 ]  The protein physically interacts with pathogens, causing "bacterial cell coating" that inhibits the  epithelial sodium channel  of bacteria, makes bacteria like  Pseudomonas  more permeable, and attracts  macrophages  and  neutrophils  for a bactericidal effect.   [ 19 ] [ 20 ]  As such, BPIFA1 plays a role in  innate immune defense  in the airways.


BPIFA1/PLUNC's ability to regulate ENaC is pH-sensitive and fails in acidic  cystic fibrosis  airways. [ 21 ]   Thus, defective  BPIFA1/PLUNC1  gene function is thought to contribute to the development of lung pathology in cystic fibrosis patients.


It may also serve as a potential molecular marker for detection of  micrometastasis  in  non-small-cell lung cancer . [ 22 ]


NM_080574 NM_001319164


NP_001306093 NP_542141


BPI fold containing family A, member 2  (BPIFA2), also known as  Parotid Secretory Protein  (PSP), is a  protein  that in humans is encoded by the  BPIFA2  gene. [ 5 ]  The  BPIFA2  gene sequence predicts multiple  transcripts  ( splice variants ); 2 mRNA variants have been well characterized. The resulting BPIFA2 is a secreted protein, expressed at very high levels in the parotid ( salivary ) gland; at high levels in oropharyngeal  mucosa , including tongue; and at moderate levels many other tissue types and glands including mammary gland, testis, lung, bladder, blood, prostate, adrenal gland, kidney, and pancreas. [ 6 ]


BPIFA2 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 7 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 8 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant  homologs  in non-vertebrate species such as insects, mollusks, and roundworms. [ 9 ] [ 10 ]  Within that broad grouping is the BPIF gene family whose members encode the BPI fold  structural motif  and are found clustered on a single chromosome, e.g.,  Chromosome 20  in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes  BPIFA1 ,  BPIFA2 ,  BPIFA3 , and 1 pseudogene  BPIFA4P ; while BPIFB consists of 5 protein encoding genes  BPIFB1 ,  BPIFB2 ,  BPIFB3 ,  BPIFB4 ,  BPIFB6  and 2 pseudogenes  BPIFB5P ,  BPIFB9P . What appears as pseudogenes in humans may appear as fully functional genes in other species.


In humans, the  BPIFA2  gene was first identified as a human  PLUNC -related gene. [ 11 ]  It had been identified shortly before as human  PSP [ 12 ]  and nearly a decade and half earlier as the mouse  PSP  gene. [ 13 ]


The function of PSP had remained unknown for many years until it was finally recognized to be within the BPI/LBP/PLUNC family, and then the bactericidal properties of that family was recognized for BPIFA2/PSP/SPLUNC2. [ 14 ]  It is primarily secreted into saliva and is therefore among the first line of defense against pathogens entering the mouth. BPIFA1 can bind to  lipopolysaccharide  (LPS) on bacteria and induce clumping  agglutination  of bacteria, a major antibacterial function for salivary proteins. [ 15 ]  For example, BPIFA2 protein was shown to inhibit the growth of  Pseudomonas aeruginosa , although it did not cause agglutination of these bacteria. [ 16 ]


Like BPIFA1/PLUNC which acts as a surfactant to lower the surface tension in mucosal fluids, BPIFA2/PIP also is a crucial surfactant in saliva. When the gene is silenced in a  knockout mouse , the saliva exhibits the surface tension of water. [ 17 ]  Further, without BPIFA2/PIP, levels of LPS in saliva were lower than in normal mice and the knockout mice exhibited signs of endotoxemia, suggesting bacteria were bypassing the first line of defense and passing into the digestive tract to cause mild inflammation.


NM_001042439 NM_178466


NM_001291079 NM_028528


NP_001035904 NP_848561


NP_001278008 NP_082804


BPI fold containing family A, member 3  (BPIFA3) is a  protein  that in humans is encoded by the  BPIFA3   gene . [ 5 ]  The gene is also known as  SPLUNC3  and  C20orf71  in humans and the  orthologous  gene in mice is  1700058C13Rik . [ 6 ]  There are multiple variants of the BPIFA3 projected to be a secreted protein. [ 7 ]  It is very highly expressed in  testis  with little or no expression in other tissues. The Human Protein Atlas project [ 8 ]  and Mouse ENCODE Consortium [ 9 ]  report  RNA-Seq  expression at RPKM levels (reads per kilobases of transcript per 1 million mapped reads ) of 29.1 for human testis and 69.4 for mouse, but 0 for all other tissues. [ 5 ] [ 6 ]  Similarly, the Bgee consortium, [ 10 ]  using multiple techniques in addition to RNA-Seq, reports a relative Expression Score of 95.8 out of 100 for testis and 99.0 for sperm in humans; however low levels of BPIFA3 between 20 and 30 were seen for a variety of tissues such as muscle, glands, prostate, nervous system, and skin. [ 11 ]


BPIFA3 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 12 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 13 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant  homologs  in non-vertebrate species such as insects, mollusks, and roundworms. [ 14 ] [ 15 ]  Within that broad grouping is the BPIF gene family whose members encode the BPI fold  structural motif  and are found clustered on a single chromosome, e.g.,  Chromosome 20  in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes  BPIFA1 ,  BPIFA2 ,  BPIFA3 , and 1 pseudogene  BPIFA4P ; while BPIFB consists of 5 protein encoding genes  BPIFB1 ,  BPIFB2 ,  BPIFB3 ,  BPIFB4 ,  BPIFB6  and 2 pseudogenes  BPIFB5P ,  BPIFB9P . What appears as pseudogenes in humans may appear as fully functional genes in other species.


In humans, the  BPIFA3  gene was first identified as a human  PLUNC -related gene [ 16 ]  and later in mouse as 1700058C13Rik. [ 17 ]  Both were recognized as BPIF gene family members and were renamed  BPIFA3  and  Bpifa3 , respectively.


Little is known about BPIFA3's function. Due to its high degree of similarity to other members of the BPI/LBP/PLUNC superfamily, it is predicted to have binding activity to lipids such as  phospholipids  and  lipopolysaccharides  but this has never been confirmed. [ 18 ]


A putative function of BPIFA3 in bacterial host defense has been suggested. Despite a near-exclusive expression of BPIFA3 in testis, only a single report implicates it in any normal or pathological states and that involves  Otitis media  (OM) in the ear. [ 19 ]  OM is a common disease of early childhood characterized by inflammation of the middle ear cavity and an effort was made to identify genetic risk factors. A  genome-wide association study  was done in the "Raine Study," a longitudinal  birth cohort  of 2,868 children in which 1532 blood samples drawn at 1,2, and 3 years of age were analyzed for gene expression correlated to a susceptibility to OM. Unexpectedly,  BPIFA3  and  BPIFA1  were the top hits, along with  CAPN14  and  GALNT14  genes, none of which has previously been implicated in OM. The investigators noted that BPIF gene family members encode proteins involved in the early recognition of bacterial pathogens as part of the host defense at the nasopharyngeal, oral and lung entrances, and that expression of  BPIFA3  and  BPIFA1  may be a logical consequence of chronic bacterial presence in the  pus  filled, OM infected ear.


NM_001012392 NM_153418


NP_001012392 NP_700467


BPI fold-containing family B member 1  (BPIFB1) is a  protein  that in humans is encoded by the  BPIFB1   gene . [ 5 ]  BPIFB1 is a secreted protein, expressed at very high levels in  mucosa  of the airways (respiratory and olfactory  epithelium ) and salivary glands, and at moderate levels in the digestive tract (tongue, stomach, intestinal epithelium) and pancreas. [ 6 ]


BPIFB1 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 7 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 8 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


BPIFB1  was also identified as the  LPLUNC1  gene (long-palate lung and nasal epithelium clone 1) in mouse, [ 11 ]  but subsequently PLUNC proteins were classified as a subfamily of the BPI fold superfamily. [ 10 ]  In a systematic analysis of the chicken genome, the  Lplunc1(Bpifb1) /  Lplunc5(Bpifb5)  branch of the gene family was determined to be absent, therefore BPIFB1 and BPIFB5 proteins likely arose only after the speciation of mammals. [ 12 ]


In mammals, the BPIFB1 protein is involved in the innate immune response to bacterial exposure in the  mucosa  of the mouth, nasal cavities, lungs, and digestive tract. [ 13 ]  It has a role in sensing and responding to Gram-negative bacteria and contributes to anti-bacterial activity.


In humans it is abnormally expressed in a respiratory diseases such as  cystic fibrosis  (CF),  chronic obstructive pulmonary disease  (COPD), and  asthma . [ 13 ]  It is also differentially in tumors such as  nasopharyngeal carcinoma  (NPC),  gastric cancer , salivary gland tumors, and  lung cancer  therefore BPIFB1 has been considered to be a therapeutic target for these conditions. For example, BPIFB1 expression is suppressed in NPC but when the gene is over-expressed in cell cultures and in mice, tumor cell migration  and invasion (metastases) is reduced. [ 14 ]


BPI fold-containing family B, member 2 , (BPIFB2) also known as  bactericidal/permeability-increasing protein-like 1 , (BPI-like 1) is a  protein  that in humans is encoded by the  BPIFB2   gene . [ 5 ] [ 6 ]


BPIFB2 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 7 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 8 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


In humans, the  BPIFB2  gene was first identified as a  BPIL3  gene  [ 5 ]  whose encoded protein was called LPLUNC2 (long-palate lung and nasal epithelium clone 2), [ 11 ]  but subsequently PLUNC proteins were classified as a subfamily of the BPI fold superfamily. [ 10 ]  In humans, the  BPIFB2  gene is found with other members of the BPI/LBP/PLUNC superfamily in a cluster on Chromosome 20.


The BPIFB2 protein is involved in the innate immune response to bacterial exposure in the mucosa of the mouth, nasal cavities, and lungs, like other closely related BPIFB proteins. In particular, it is highly expressed in normal salivary glands and esophagus as well as in  hypertrophic  tonsils in humans. [ 6 ]  In chronic rhinosinusitis BPIFB2/LPLUNC2 levels are profoundly reduced which has been interpreted as a defect in the release of glandular innate defense molecules. [ 12 ]


NM_182658 NM_001376932


NM_194357 NM_001379473


NP_872599 NP_001363861


NP_919338 NP_001366402


BPI fold containing family B, member 3  (BPIFB3) is a  protein  that in humans is encoded by the  BPIFB3   gene . [ 5 ]  Two variants have been detected in humans. [ 6 ] [ 7 ]


BPIFB3 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 8 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 9 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant  homologs  in non-vertebrate species such as insects, mollusks, and roundworms. [ 10 ] [ 11 ]  Within that broad grouping is the BPIF gene family whose members encode the BPI fold  structural motif  and are found clustered on a single chromosome, e.g.,  Chromosome 20  in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes  BPIFA1 ,  BPIFA2 ,  BPIFA3 , and 1 pseudogene  BPIFA4P ; while BPIFB consists of 5 protein encoding genes  BPIFB1 ,  BPIFB2 ,  BPIFB3 ,  BPIFB4 ,  BPIFB6  and 2 pseudogenes  BPIFB5P ,  BPIFB9P . What appears as pseudogenes in humans may appear as fully functional genes in other species.


BPIFB3  was first directly identified in a screen of rat olfactory epithelium as  RYA3 [ 12 ]  and was recognized to be a member of the BPI fold superfamily. [ 13 ] [ 11 ]  In humans, it was formerly known as "Long palate, lung and nasal epithelium carcinoma-associated protein 3" encoded by the  LPLUNC3  gene. The  BPIFB3  gene is found with other members of the BPIF gene family in a cluster on chromosome 20.


BPIFB3/RYA3 is highly expressed in olfactory epithelium and the tongue, [ 12 ] [ 13 ]  within the cytoplasm of cells, and is thought to be similar to an  odorant binding protein  which presents  odorant  molecules to chemical odorant receptor molecules. [ 14 ]


Like other BPI-fold family members involved in defense from infection, BPIFB3 may be involved in responses to viral infections such as the  enteroviruses   coxsackievirus B  and  poliovirus  in epithelial and endothelial tissue. [ 15 ] [ 16 ]  Its cytoplasmic location appears to be localized to the  endoplasmic reticulum  (ER) and influences the replication of coxsackievirus B; when BPIFB3 is knocked out in experimental systems coxsackievirus B replication dramatically increases. It has been within observed in the ER to be physically associated with another family member, BPIFB6, and modulation of either of these two proteins can enhance or suppress enteroviral release from cells.  [ 17 ]


BPI fold containing family B, member 4  (BPIFB4) is a  protein  that in humans is encoded by the BPIFB4  gene . [ 5 ]  It was formerly known as "Long palate, lung and nasal epithelium carcinoma-associated protein 4" encoded by the  LPLUNC4  gene. The  BPIFB4  gene sequence predicts 4  transcripts  ( splice variants ); 3  isoforms  have been well characterized. [ 6 ] [ 7 ]    In a variety of mammals, BPIFB4 is generally expressed in very high levels in the  olfactory epithelium  (nasal  mucosa ), high levels in the  gonads  ( testis ,  ovary ) and  pituitary , moderate levels in white blood cells ( monocytes ) [ 8 ] [ 9 ] [ 10 ] [ 11 ]  It can occur either localized in the cytoplasm of cells or secreted and circulated systemically in blood plasma.


BPIFB4 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 12 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 13 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


BPIFB4 occurs as 3 separate  isoforms  in humans. [ 7 ]  These isoforms were discovered in a  genome-wide association study  of  centenarians  that revealed 3  haplotypes  of the  BPIFB4  gene:  wild-type (WT-BPIFB4), a longevity-associated variant (LAV-BPIFB4) with a 29%  allele  frequency, and a rare variant (RV-BPIFB4) with a 5% allele frequency. [ 16 ]  The  BPIFB4  gene is found with other members of the BPIF gene family in a cluster on chromosome 20 in humans.


BPIFB4 protein is normally expressed in olfactory epithelium,  mononuclear cells  and  macrophage -like cells as well as a variety of progenitor/stem cell types. [ 17 ]  In the olfactory  mucosa  it is believed to act similarly to other BPIFB proteins in the innate immune response to bacterial exposure. BPIFB4 found circulating in the bloodstream is believed to interact with  endothelial cells  lining blood vessels which subsequently results in a vasorelaxation of the  smooth muscle  cells of blood vessels.


In individuals with high circulating levels of LAV-BPIFB4, it appears to be cardioprotective [ 17 ] [ 18 ]  and immunodulatory ( anti-inflammatory ). [ 19 ]  In a study of long-living individuals (LLI), the circulating plasma levels of PBIB4 protein was compared between middle aged individuals (45–59 years old), healthy LLI (95–97 years old), and frail LLI (96-99 year old). Circulating BPIB4 was much higher in the healthy LLI group (824 pg/mL) compared to middle aged controls (133 pg/mL) and the frail LLI group (21 pg/mL). [ 20 ]


LAV-BPIFB4 is believed to be cardioprotective due to overall improved endothelial cell function, lowering blood pressure and improving  revascularization  when cardiac tissue may be compromised. [ 18 ]  This effect arises from a cascade of biochemical events. WT-BPIFB4 and LAV-BPIFB4 have different subcellular localization; WT-BPIFB4 localizes to the cell nucleus while LAV-BPIFB4 is cytoplasmic. [ 7 ]  LAV-BPIFB4 in the  endoplasmic reticulum  (ER) is  phosphorylated  by  Protein Kinase R  (PKR) which results in enhanced protein unfolding, reduced ER stress, and overall improved cellular  homeostasis . In addition to phosphorylation by PKR, LAV-BPIFB4 can be phosphorylated by  Protein Kinase C alpha . In either case, when LAV-BPIFB4 becomes phosphorylated in the  cytosol , it can then interact with  14-3-3 protein  and  Heat Shock Protein 90 , forming a complex. This complex, in turn, activates eNOS. Activated eNOS produces  nitric oxide  which causes  vasorelaxation  of smooth muscle cells in blood vessels throughout the circulatory system, lowering blood pressure. Furthermore, increased nitric oxide from activated eNOS promotes the sprouting of new capillaries ( angiogenesis ) in conditions when ischemia occurs [ 21 ]  caused by the blockage of arteries by  atherosclerosis , for example.


LAV-BPIFB4 is believed to be immunomodulatory due to a variety of mechanisms involving macrophages and monocytes that can counteract low-grade chronic inflammatory conditions. [ 19 ]  BPIFB4 induces a  M2 macrophage polarizing  effect which helps resolve inflammation, help tissue healing, and tolerate  self-antigens . BPIFB4 induces a redistribution of circulating monocytes from classical monocytes (CD14++CD16-) to non-classical monocytes (CD14++CD16++), normally elevated in patients with coronary artery disease but in this case thought to patrol the vasculature and remove damaged cells in several disease conditions, thereby aiding tissue healing. BPIFB4 also reduces  T-cell  activation demonstrated by suppression of T cell proliferation and elevation of circulating levels of  interleukins  IL-23, IL-27 and atheroprotective IL-33. [ 22 ]


BPI fold containing family B, member 6  (BPIFB6), also known as  bactericidal/permeability-increasing protein-like 3  (BPIL3), is a  protein  that in humans is encoded by the  BPIFB6   gene , also known as  BPIL3  and  LPLUNC6 . It is expressed at high levels in  hypertrophic   tonsils , [ 5 ]  at relatively moderate levels in oronasal  epithelium  including nasal  mucosa , tongue, and  salivary gland , as well as  esophageal  mucosa at lesser levels. [ 6 ]   Orthologs  are present in many vertebrate species including mammals, birds, reptiles, and amphibians. [ 7 ]


BPIFB6 is a member of a BPI fold  protein superfamily  defined by the presence of the bactericidal/permeability-increasing protein fold (BPI fold) which is formed by two similar domains in a "boomerang" shape. [ 8 ]   This superfamily is also known as the  BPI/LBP/PLUNC  family or the  BPI / LPB / CETP  family. [ 9 ]  The BPI fold creates apolar binding pockets that can interact with hydrophobic and  amphipathic  molecules, such as the acyl carbon chains of  lipopolysaccharide  found on  Gram-negative bacteria , but members of this family may have many other functions.


Genes for the BPI/LBP/PLUNC superfamily are found in all vertebrate species, including distant  homologs  in non-vertebrate species such as insects, mollusks, and roundworms. [ 10 ] [ 11 ]  Within that broad grouping is the BPIF gene family whose members encode the BPI fold  structural motif  and are found clustered on a single chromosome, e.g.,  Chromosome 20  in humans, Chromosome 2 in mouse, Chromosome 3 in rat, Chromosome 17 in pig, Chromosome 13 in cow. The BPIF gene family is split into two groupings, BPIFA and BPIFB. In humans, BIPFA consists of 3 protein encoding genes  BPIFA1 ,  BPIFA2 ,  BPIFA3 , and 1 pseudogene  BPIFA4P ; while BPIFB consists of 5 protein encoding genes  BPIFB1 ,  BPIFB2 ,  BPIFB3 ,  BPIFB4 , BPIFB6 and 2 pseudogenes  BPIFB5P ,  BPIFB9P . What appears as pseudogenes in humans may appear as fully functional genes in other species.


The  BPIFB6  gene was first identified in humans as  BPIL3  based on sequence homology [ 5 ]  and was immediately recognized to be a member of the BPI fold gene superfamily.


BPIFB6 may function as a regulator of  secretory pathway  trafficking within cells, which in turn may help regulate virus infections. BPIFB6 has been assumed to be a secreted protein, based on the similarity of its gene sequence to other family members that are secreted. [ 12 ]  But it has been demonstrated in one study to be located in the  endoplasmic reticulum  (ER). [ 13 ]  The ER exists as a network of sheets and tubules and BPIFB6 was found to localize primarily to ER sheets where it interacts with two other PBI fold family members,  BPIFB2  and  BPIFB3 . Further, silencing of the BPIFB6 gene caused dramatic changes in the morphology of the  Golgi complex , Golgi fragmentation, and disruption of normal cytoplasmic vesicles. This all points to a role for BPIFB6 in secretory pathway trafficking, which was further illustrated by its effects on viral replication. Viruses such as coxsackievirus B (CVB) and poliovirus (PV) co-opt the host cell's secretory pathway, which controls the transport of proteins from the endoplasmic reticulum to the Golgi complex, to facilitate their  replication . When the BPIFB6 gene was silenced, CVB and PV replication was blocked.


BPIFB6's association with mucosa containing tissues re-emerged in a study of biomarkers in rectal cancer. In an epigenome-wide analysis of  DNA methylation , BPIB6/BPIL3 was one of two genes were significantly hypomethylated. [ 14 ]  Also, tonsils which are mucosal lymphatic tissues, can become enlarged (hypertrophic) following inflammation from infection and recurrent  pharyngitis  (sore throat). Hypertrophic tonsils have been shown to have highly elevated expression of BPIFB6/BPIL3. [ 5 ]


Brain-specific homeobox  is a  protein  that in humans is encoded by the  BSX   gene . [ 1 ]


Bsx is an evolutionarily highly-conserved homeodomain-containing transcription factor that belongs to the ANTP-class. [ 2 ]  In mouse it has been shown to be expressed in the  telencephalic septum ,  pineal gland , the  mammillary bodies  and  arcuate nucleus . [ 3 ]


In the hypothalamic  arcuate nucleus , Bsx has been demonstrated to be necessary for normal expression levels of the two  orexigenic   neuropeptides   Agouti-related peptide  and  Neuropeptide Y . [ 4 ]


In the  pineal gland  of the clawed frog  Xenopus , Bsx is expressed following the  circadian rhythm  and controls  photoreceptor cell   differentiation . [ 5 ]  In  zebrafish  Bsx is required for normal development of all cell types within the  pineal gland , including  melatonin -releasing pinealocytes,  photoreceptor cells  and leftwards migrating parapineal cells, [ 6 ]  which in zebrafish are crucial for the establishment of  brain asymmetry . [ 7 ]


NM_152743 NM_001350626 NM_001350627


NM_001276287 NM_172724 NM_181066


NP_689956 NP_001337555 NP_001337556


NP_001263216 NP_851411


BRCA1-associated ATM activator 1  is a  protein  in humans that is encoded by the BRAT1  gene . [ 5 ]


The protein encoded by this ubiquitously expressed gene interacts with the tumor suppressing  BRCA1  (breast cancer 1) protein and the  ATM  ( ataxia telangiectasia  mutated) protein. ATM is thought to be a master controller of  cell cycle checkpoint  signalling pathways that are required for cellular responses to  DNA damage  such as  double-strand breaks  that are induced by ionizing radiation and complexes with BRCA1 in the multi-protein complex BASC (BRAC1-associated genome surveillance complex). The protein encoded by this gene is thought to play a role in the DNA damage pathway regulated by BRCA1 and ATM. [ 5 ]


This article on a  gene  on human  chromosome 7  is a  stub . You can help Wikipedia by  expanding it .


Uncharacterized protein C2orf27  is a  protein  that in humans is encoded by the  C2orf27A  gene . Although its function is not clearly understood, through the use of bioinformatic analysis more information is being brought to light.


The  mRNA  is 1,222bp in length and is located at 2q21.2 with a total of five exons in  Homo sapiens . [ 1 ] [ 2 ]  Other sources list  C2orf27B  as a paralog but this is unlikely because both genes are located in the same place on  chromosome 2 . [ 3 ]  It seems to be generally accepted that they are the same gene. [ 1 ]  Other gene aliases include  C2orf27  and chromosome 2  open reading frame  27A. The gene is surrounded upstream by POTEKP and downstream by  ANKRD 30BL.


The length of the C2orf27 protein sequence is 203 a.a. in length and has a molecular weight of 21.5 kDa with a  pI  of 5.13 in  Homo sapiens . [ 4 ] [ 5 ]  When taking into account the primate orthologs, the molecular weights range from 21.4 to 36.7 kDa with the  isoelectric point  ranging from 4.58 to 5.25. [ 6 ] [ 5 ]  This gene is located in the nucleus of the cell and, it doesn't contain any transmembrane regions. [ 7 ] [ 8 ]


Looking at the motifs of the protein sequence, a few important ones are present. All of the repeat sequences are concentrated near the N-terminus of the protein and are highly conserved through all the orthologs.


Post-translationally, there are multiple  glycosylation  sites scattered throughout the protein sequence,  phosphorylation  site positioned at S13, and a  nuclear export signal  located at L80 - V90, which also happens to be within a  coiled coil  region.


C2orf27 is ubiquitously expressed in most tissues but with increased expression in the brain, pancreas, kidneys, and testis. [ 9 ] [ 10 ]


The protein is said to interaction with another protein called  ataxin-1  which was discovered by performing a two hybrid prey pooling (Y2H) approach. [ 11 ]
They share the similar characteristics of being located in the nucleus of cells and are expressed in the brain.


The overall structure of this protein is predicted to be composed of both alpha-helices and beta-sheets. The majority of the alpha-helices fall on the N-terminus of the protein and the beta-sheets fall near the C-terminus of the protein. There is a sequence of four prolines located from P185 to P188 has the secondary structure of a type II  polyproline helix .


This gene is found in primates but is also found at a very poor E-values in other mammals and organisms like fish, invertebrates, fungi, bacteria, or plants. The protein C2orf27, however, is strictly found only in primates like  chimpanzees ,  gorillas , and baboons.


When comparing the mRNA of  C2orf27A  with the exclusion of primates, it is shown that there is a high similarity with a gene called neurobeachin (NBEA)  NBEA . When taking a look at this connection between the two, it was found that NBEA was on a different reading frame than  C2orf27A  which already begins to rule out any similarity between the two. This was confirmed based upon the fact that when comparing both of these protein sequences, it resulted in a 44% similarity in a 1% query cover. These protein sequences are entirely different suggesting that their functions may not be similar. It was also discovered when comparing the alignment of the sequences, it was shown that a duplication event occurred between NBEA and  C2orf27A . NBEA is present on  chromosome 13  but a section of this mRNA corresponds, with a 96% similarity score, with exons one through four on C2orf27 of chromosome 2. [ 1 ]  This may be an example of a  gene duplication  event.


Taking all of this into account, the duplication of NBEA into chromosome 2 to form C2orf27 may be the divergence point of the gene becoming strictly present in primates only.


C2orf27A has been found to be associated with nonsyndromic  craniosynostosis , a premature fusion of the  calvaria . There are two distinct subtypes of this disease and patients with a certain subtype present with an increase in the expression of certain genes characteristic of each subtype. There is subtype A which is associated with increased  insulin-like growth factor  expression, and subtype B which is associated with increased  integrin  expression. There is an increased expression of the gene C2orf27A shown in patients with the subtype B disease. [ 12 ]


Through a combination of a microarray assay and use of IPA software, C2orf27A has been found to be regulated by the hormone melatonin and linked with a role in cellular movement, the function and development of blood and bone marrow, and cell-mediated response of the immune system. [ 13 ]


The  chimeric  fusion of C2orf27A (exon 1) and NBEA (exon 37 and 38) was present in only ovarian cancer samples. [ 14 ]


NM_001144992 NM_001144993


NP_001138464 NP_001138465


C2orf72  (Chromosome 2, Open Reading Frame 72)  is a gene in humans ( Homo sapiens )  that encodes a  protein  currently named after its gene,  C2orf72 . [ 5 ]  It is also designated LOC257407 [ 5 ]  and can be found under GenBank accession code NM_001144994.2. [ 6 ]  The protein can be found under UniProt accession code A6NCS6. [ 7 ]


This gene is primarily expressed in the liver, brain, placental, and small intestine tissues. [ 8 ]  C2orf72 is an intracellular protein that has been predicted to reside within the  nucleus ,  cytosol , and  plasma membrane  of cells. [ 5 ]   The function of C2orf72 is unknown, but it is predicted to be involved in  very-low-density lipoprotein  particle assembly and also involved in the regulation of  cholesterol  esterification. [ 9 ]  This prediction also matches with the fact that both estradiol [ 10 ]  and testosterone [ 11 ]  have been reported to upregulate expression of C2orf72. [ 12 ]


C2orf72  is a protein-coding gene found on the forward (+) strand of chromosome 2 at the locus 2q37.1, on the long arm of the chromosome. [ 5 ]


C2orf72's  mRNA transcript is reported to be about 3,629 base pairs long. [ 6 ]  It appears to have two  polyadenylation  sites near the 5′ end of the mRNA transcript, each preceded by their respective regulatory sequences, such as ATTAAA or AATAAA. [ 6 ]


There are three predicted exons reported for human  C2orf72 . [ 6 ]


C2orf72  is preferentially expressed in  brain ,  liver ,  placenta ,  colon ,  small intestine ,  gallbladder ,  stomach , and  prostate , and to a lesser extent in  adrenal gland ,  appendix ,  pancreas ,  lung ,  kidney ,  testis , and  urinary bladder . [ 8 ]


It is predicted via Archs4 [ 13 ]  (July 16, 2022) that the function of this gene may be related to  very-low-density lipoprotein  particle assembly [ 14 ]  and also involved in the regulation of  cholesterol  esterification. [ 9 ]


In a study of embryonic liver samples lacking hepatocyte nuclear factor 4 alpha (HNF4α), the expression of C2orf72 was downregulated. [ 15 ]


Both estradiol [ 10 ]  and testosterone [ 11 ]  upregulate expression of C2orf72. [ 12 ]


C2orf72 mRNA and protein products are found preferentially in the liver, kidney, and placenta. [ 16 ]  The protein is localized to the cell membrane and cytoplasm in liver, brain, and placental tissues. [ 16 ]


miR-1271-5p is a microRNA that could bind to the 3′ untranslated region of the  C2orf72  mRNA transcript at 5′-...GUGCCAA...-3′. [ 6 ] [ 17 ] [ 18 ]


There are at least two predicted phosphorylation sites for the human C2orf72 protein, one at threonine-286 and the other at serine-294. [ 7 ]


The predicted molecular weight of C2orf72 is 30.5 kDa, [ 19 ]  and it has a predicted  isoelectric point  (pI) of pH 8.7. [ 20 ]


There are eight cysteine residues, for a potential of four disulfide bonds. [ 21 ]  Most of the cysteine residues are positioned next to a polar amino acid (uncharged or positively or negatively charged). [ 21 ]


At physiological pH, there are 33 positively charged amino acid residues, including histidine, most of which are arginines. [ 21 ]  Likewise, there are 33 negatively charged amino acid residues, most of which are glutamates. [ 21 ]


There are 14 hydroxyl-containing residues (tyrosine, threonine or serine) that could serve as  typical phosphorylation sites ; most of these are serines. [ 21 ]


These proteins have been reported to interact with human C2orf72: RASN (GTPase NRas), [ 23 ]  RASK (GTPase KRas), [ 23 ]  and CD81. [ 24 ] [ 25 ]


There are at least 203 organisms with an ortholog of C2orf72. [ 26 ]  The most evolutionarily distant reported ortholog of C2orf72 is in the Australian ghost shark ( Callorhincus milii );, [ 27 ] [ 28 ] [ 29 ]  and it is broadly conserved from Actinopterygii (bony fish) to Mammalia.


(million years ago)


code


length


similarity (%)


triunguis


Chromosome 5 open reading frame 52  ( C5orf52 ) is a  gene  of unknown function. It encodes the  protein   A6NGY3 . The C5orf52 gene is strongly predicted to be localized in the  cytoplasm . [ 5 ]


This gene is found on the positive strand of chromosome 5 (5q33.3) which spans a total of 9218 nucleotides that make up the gene. [ 6 ]  C5orf52 codes for 2  introns  and 3  exons  with 537 base pairs of this gene being antisense to splice gene SOX30, which raises the possibility of regulated alternate expression. [ 7 ]


There are multiple sources that predict C5orf52 being tissue-specific in normal tissues. [ 8 ]  It was expressed in the appendix,  brain , colon, duodenum, endometrium, gall bladder, kidney,  lung , lymph node,  prostate ,  small intestine , spleen, urinary bladder, and was expressed in higher levels in the  testis .


There is only one known isoform (C5orf52 isoform X1). [ 9 ]  Its sequence has a length of 1023 base pairs that encodes for 3 exons. Transcription starts at the 385th base pair and stops at the 864th base pair. This gene contains both a  5' UTR  (length of 387 nucleotides) and a  3' UTR  (length of 162 nucleotides). [ 10 ]


The DUF5528 A6NGY3 is encoded by the C5orf52 gene and has a length of 159 amino acids. [ 11 ] [ 12 ]  The molecular mass is 17.9 kDa and the  isoelectric point  is 10.8. [ 13 ] [ 14 ]


Although the exact function of C5orf52 is unknown in humans, there is large evidence for the gene being associated with  Spermatogenesis  as there is very high expression in the testis, with lowered expression in the brain, colon, duodenum, and small intestine.
 [ 15 ]
C5orf52 does not have any  transmembrane domains  or signal sequences. [ 16 ]


The protein is slightly  serine  rich, which is concentrated towards the beginning of the residue, and is overall slightly deficient in  aspartic acid . [ 17 ]  The distribution of charged positive and negative  amino acids  in the protein are equally spread out and result in no big charged clusters. [ 18 ]  The predicted  tertiary structures  of the human protein were compiled with the use of multiple bioinformatic tools. All of the tools aided in predicting the protein to contain a long string of alpha helices near the  C-terminus  and extended strands near the  N-terminus . [ 19 ] [ 20 ]


Different sites were identified to be present on the protein and these include: N-myristoylation site, amidation site, N-glycosylation site, cAMP- and cGMP-dependent protein kinase phosphorylation site, Casein kinase II phosphorylation site, and  protein kinase C  phosphorylation site. [ 21 ]  Other areas of the protein were predicted phosphorylation sites in Serine, Threonine, and Tyrosine. [ 22 ]  Only two Serines and one Threonine were strongly conserved with close orthologs.


There are no predicted  paralogs  for C5orf52 in  Homo sapiens .


Orthologs  were found by comparing the C5orf52 gene across NCBI’s database with different species' genetic codes. Twenty organisms from a variety of orders were selected to compare and further investigate. [ 23 ]  These species included  mammals , reptiles, amphibians, birds, and an invertebrate. The data in the table was sorted by the sequence percent identity to the human protein and then sorted by date of divergence.


Orthologs of Homo sapiens C5orf52. Data is sorted by sequence identity and then date of divergence. Shading is associated with the grouping of organisms


The oldest orthologs of human c5orf52 was found in  Paralvinella palmiformis , which is an invertebrate with a date of divergence of around 686 million years ago. [ 24 ]  The length of the tree branch or the amount of time seems to be smaller with orthologs closer to the Humans. The upper cluster of animals are all mammals, which would follow the trend with similar identities being correlated to a smaller distance away from the gene in humans. The length of the branch is proportional to the date of divergence from humans.


Phylogenetic Tree containing ortholog species to the Human gene C5orf52. Tree is in Radial format meaning the distance of the line from the main branch describes species divergence. Source Phylogeny.fr [ 25 ]


When the human  cytochrome C  and  fibrinogen alpha chain  sequences were compared to its orthologs, the protein m (corrected percent divergence) trendline was very similar to that of the fibrinogen alpha chain. Fibrinogen alpha chain sequence has a fast rate of change over time, which indicates that human c5orf52 does as well.


Multiple sequence alignments indicated amino acid residue conservation throughout the C5orf52 with close orthologs. The most highly conserved regions spanned throughout the middle of the protein around amino acid 90 and had strong clumped conservation towards the C-terminus, which didn't have strong conservation.


C5orf52 is not predicted to have any binary interactions with proteins. [ 26 ] [ 27 ]  The true reason for this is unknown at this point. One possible explanation is the lack of any transmembrane domains. It may also be because of the lack of information on C5orf52. It may play a role in specialized pathways and conditions that aren’t explored yet in the database. A neighboring gene, upstream on the negative strand,  SOX30 , was found to have 63 binary interactions on PSICQUIC. [ 28 ]


NM_001010940 NM_001308084 NM_001308085 NM_001308086


NP_001010940 NP_001295013 NP_001295014 NP_001295015