Clavesin-2 (CLVS2) is a protein-coding gene located on chromosome 6 in humans. The protein belongs to the clavesin family of neuronal proteins and is expressed in the nervous system. CLVS2 contains a lipid-binding Sec14 domains and a CRAL-TRIO family of lipid binding.
Gene The CLVS2 gene is located on the long arm of chromosome 6 (6q22.31) between base pairs 1222,996,235 - 123,072,925 on the forward strand The gene is approximately 77kb of genomic DNA. The gene has multiple exons and produces splice variants alternatively.
The CLVS2 gene produces multiple transcript alternative splicing variants XM_001010852.4 & MN_047418196.1. These transcripts contribute to difference in intracellular localization or regulation of the protein. Research shows that elevated CLVS2 mRNA expression in the neuronal tissues relative to other tissues within humans.The longest transcript encodes the protein sequence represent by NP_001010852.2.
Cellular distribution CLVS2 primarily localizes to the cytoplasm and is enriched on Clathrin-coated vesicles. Evidence predicted localization to the cytoplasm with a 73.9% confidence, 17.4% to the nucleus, and 8.7% to the mitochondria. CLVS2 co-localize with markers of endosomes and the trans-Golgi network (TGN), as well as with adaptor protein-1.
Structure
The size of the protein NP_001010852.2 is 327 amino acids. It also binds to phosphatidylinositol 3,5-bisphosphate (Ptdins(3,5)P2). The human CLVS2 protein has a predicted molecular wight of 38.0 kdal. The theoretical isoelectric (pI) is 5.97 which is considered acidic.
There are 6 motif domains important to the human CLVS2, which are the CRAL-TRIO lipid-binding domains within the central region.
Function
Clavesin-2 gene is involved in membrane organization and vesicle dynamics. The expression of CLVS2 in neuronal tissues indicates that its cellular function is specialized within the nervous system. CLVS2 contributes to trafficking pathways required for neuronal maintenance and synaptic function.
The structural biochemistry of CLVS2 suggest that it has a globular fold with several alpha-helical regions surrounding a central core
Interacting proteins
There are 4 major CLVS2 protein interacting partners such as AP1S1, AP1M1, AP1G1, CLTC (Clathrin Heavy Chain). CLVS2 has several identified proteins associated with vesicle trafficking and intracellular transport with the presence of the CRAL-TRIO lipid-binding domain . This suggest that CLVS2 participates in intracellular mediated trafficking. ProteinNameRelationship to CLVS2FunctionAP1S1Adaptor Related Protein Complex 1 Sigma 1 AP1S1 is part of the AP-1 adaptor complex that sorts proteins into transport vesiclesVesicle traffickingAP1M1Adaptor Related Protein Complex Mu 1AP1M1 recognizes cargo proteins destined for vesicular transportCargo sortingAP1G1Adaptor Related Protein Complex 1 Gamma 1AP1G1 is a core component of the AP-1 complex Intracellular transportAP1S3Adaptor Related Protein Complex 1 Sigma 3AP1S3 functions in vesicle-mediated transport Endosomal traffickingAP1S2Adaptor Related Protein Complex 1 Sigma 2AP1S2 participates in vesicle formation between the Golgi apparatus and endosomesVesicle formationCLTCClathrin Heavy ChainCLTC forms the structural scaffold of clathrin-coated vesicles. Since clathrin-mediated transport is essential for intracellular trafficking EndocytosisNWD1NACHT and WD Repeat Domain Protein 1NWD1 is involved in protein complex assembly and signaling regulation. Signaling regulationCCD175Coiled-Coil Domain Containing 175UnknownUnknownVWC2Von Willebrand Factor C Domain Protein 2VWC2 is involved in extracellular signaling and developmental pathwaysExtracellular signaling
Regulation Gene level regulation
CLVS2 promoter identified several predicted transcription factor binding sites located within conserved noncoding regions upstream of the transcription start site. Many of the highest-scoring transcription factors, including LHX3, SP8, ZIC2, and ZIC5, are known regulators of neural development and nervous system differentiation. This finding is consistent with the strong brain-specific expression observed for CLVS2. Several zinc-finger proteins (ZNF530, ZNF93, ZFP14, and ZBED4) were also identified and likely contribute to transcriptional regulation of CLVS2 expression. Transcription FactorNameWhat does it does?ScoreReason for importanceLhx3LIM homebox 3It regulates the neuronal development and spinal cord differentiation546Neural development with CLVS brain expressionSP8Specificity protein 8 Controls the Forebrain and neuron patterning511Located in a conserved promoter regionZic2Zic Family Member 2Regulates the neural tube and brain development 511Near the binding site near the promoterZNF530Zinc Finger Protein 530Putative DNA-binding transcription regulator 514Transcriptional start region and close to the transcription start siteZNF93Zinc Finger Protein 93Transcriptional regulator involved in gene expression583Highest scoring binding site near transcription initiationZFP14Zinc Finger Protein 14Transcription regulator 514Conserved regionZBED4Zinc Finger BED-Type Containing 4Transcription regulator 502Location near transcriptional site ZIC5Zic Family Member 5Regulates neural crest and developmental signaling521Relation to neural expression and a conserved region Protein level regulation
CLVS2 exhibits tissue specific expression and is enriched within mainly the brain and prostrate. Within the brain it can be found in separate areas such as the cerebrum and the central nervous system.
The CLVS2 protein has a low abundance than other proteins. The cerebral cortex shows moderate cytoplasmic positivity in neuronal cells. This is heavily related to neuronal vesicle trafficking and synaptic function.
Homolog/ evolution The CLVS2 gene first appeared in fish, reptiles, birds, and mammals. More distant homologs identified in invertebrates suggested an ancestral form. The most distantly related species compared to humans is Drosophila Willistoni. The CLVS2 gene family contains two primary members in humans CLVS2 and CLVS1.
Paralogs
There is 1 known paralog within the human genome. Clavesin 1 (CLVS1). CLVS1Genus & SpeciesCommon NameTaxonomic GroupDivergence Time MYAAcession #Sequence Length (aa)Sequence Identity to Human Protein (%)MammalHomo sapiensHumansPrimate0NP_775790.1354100%Giraffa tippelskirchiMasai giraffeArtiodactyla94XP_081357274.135480.10%Cnephaeus nilssoniiBatChiropetra94XP_079652655.135498.00% Orthologs CLVS2Genus & SpeciesCommon NameTaxonomic GroupDivergence Time MYAAcession #Sequence Length (aa)Sequence Identity to Human Protein (%)MammalHomo sapiensHumansPrimate0NP_001010852.2327100%Mus musculusHouse MouseRodentia87NP_780657.132797.3%Desmodus rontundusVampier batPhyllostomidae94XP_024407932.232798.0%AvesMelopsittacus undulatusBudgerigarPsittaciformes319XP_005154777.132797.3%Falco cherrugSaker FalconFalconiformes319XP_005443818.432796.3%Gallus gallusRed JunglefowlGaliformes319XP_040525051.132797.3%ReptiliaPelodiscus sinensisChinese Softshell TurtleTestudinidae319XP_075780188.132797.3%Alligator mississippiensisAmerican AlligatorAlligatoridae319XP_059589422.132796.2%FishBoleophthalmus pectinirostrisGobie bony fishActinopterygii429XP_020784658.131369.4%Danio rerioZebrafishCypriniformes429NP_001020716.132988.8%Betta splendensSiamese fighting fishAnabantiformes429XP_027887306.133386.2%InvertebratePocillopora verrucosaCauliflower coralPocilloperidae685XP_058958459.030964.0%Lingula anatinaBrachiopodBrachiopoda686XP_013418372.132351.1%Drosophila willistoniFuit FliesInsecta686XP_023033937.231240.3%Nemastostella vectensisStarlet sea anemoneCnidaria685XP_001625862.333468% Mammalian orthologs exhibit greater than 95% amino acid sequence identity to the human CLVS2 protein.
Clinical significance Although CLVS2 has not been extensively characterized clinically, CLVS2 has been likened to cognitive decline and neurological disease pathways.
Research has been noted to show some link between CLVS2 and Fanconi Anemia, Complementation Group D1 (FA-D1). FA-D1 is a genomic instability syndrome typically linked to defects in the BRCA2 gene at 13q12, and the CLVS2 association may reflect proximity or co-deletion events rather than a direct causal role.
Rare coding variants in CLVS2 are associated with early stages on Alzheimer's disease A genome-wide search for loci interacting with known prostate cancer risk-associated genetic variants identified CLVS2 as a region of interest.
References