ID CTSR2_HUMAN Reviewed; 530 AA. AC Q96P56; Q8NHT9; Q96P54; Q96P55; DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot. DT 24-JUL-2007, sequence version 2. DT 27-MAR-2024, entry version 165. DE RecName: Full=Cation channel sperm-associated protein 2; DE Short=CatSper2; GN Name=CATSPER2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3), AND TISSUE SPECIFICITY. RX PubMed=11675491; DOI=10.1073/pnas.221454998; RA Quill T.A., Ren D., Clapham D.E., Garbers D.L.; RT "A voltage-gated ion channel expressed specifically in spermatozoa."; RL Proc. Natl. Acad. Sci. U.S.A. 98:12527-12531(2001). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 2 AND 4). RC TISSUE=Brain, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [3] RP INVOLVEMENT IN DIS. RX PubMed=12825070; DOI=10.1038/sj.ejhg.5200991; RA Avidan N., Tamary H., Dgany O., Cattan D., Pariente A., Thulliez M., RA Borot N., Moati L., Barthelme A., Shalmon L., Krasnov T., Ben-Asher E., RA Olender T., Khen M., Yaniv I., Zaizov R., Shalev H., Delaunay J., RA Fellous M., Lancet D., Beckmann J.S.; RT "CATSPER2, a human autosomal nonsyndromic male infertility gene."; RL Eur. J. Hum. Genet. 11:497-502(2003). RN [4] RP INTERACTION WITH CACNA1I. RX PubMed=16740636; DOI=10.1074/jbc.m511288200; RA Zhang D., Chen J., Saraf A., Cassar S., Han P., Rogers J.C., Brioni J.D., RA Sullivan J.P., Gopalakrishnan M.; RT "Association of Catsper1 or -2 with Ca(v)3.3 leads to suppression of T-type RT calcium channel activity."; RL J. Biol. Chem. 281:22332-22341(2006). RN [5] RP INVOLVEMENT IN DIS. RX PubMed=17098888; DOI=10.1136/jmg.2006.045765; RA Zhang Y., Malekpour M., Al-Madani N., Kahrizi K., Zanganeh M., Mohseni M., RA Mojahedi F., Daneshi A., Najmabadi H., Smith R.J.H.; RT "Sensorineural deafness and male infertility: a contiguous gene deletion RT syndrome."; RL J. Med. Genet. 44:233-240(2007). RN [6] RP TISSUE SPECIFICITY. RX PubMed=17347248; DOI=10.1093/molehr/gam009; RA Li H.-G., Ding X.-F., Liao A.-H., Kong X.-B., Xiong C.-L.; RT "Expression of CatSper family transcripts in the mouse testis during post- RT natal development and human ejaculated spermatozoa: relationship to sperm RT motility."; RL Mol. Hum. Reprod. 13:299-306(2007). RN [7] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=21412338; DOI=10.1038/nature09769; RA Strunker T., Goodwin N., Brenker C., Kashikar N.D., Weyand I., Seifert R., RA Kaupp U.B.; RT "The CatSper channel mediates progesterone-induced Ca2+ influx in human RT sperm."; RL Nature 471:382-386(2011). RN [8] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=21412339; DOI=10.1038/nature09767; RA Lishko P.V., Botchkina I.L., Kirichok Y.; RT "Progesterone activates the principal Ca2+ channel of human sperm."; RL Nature 471:387-391(2011). RN [9] RP ACTIVITY REGULATION. RX PubMed=26989199; DOI=10.1126/science.aad6887; RA Miller M.R., Mannowetz N., Iavarone A.T., Safavi R., Gracheva E.O., RA Smith J.F., Hill R.Z., Bautista D.M., Kirichok Y., Lishko P.V.; RT "Unconventional endocannabinoid signaling governs sperm activation via sex RT hormone progesterone."; RL Science 352:555-559(2016). CC -!- FUNCTION: Voltage-gated calcium channel that plays a central role in CC calcium-dependent physiological responses essential for successful CC fertilization, such as sperm hyperactivation, acrosome reaction and CC chemotaxis towards the oocyte. {ECO:0000269|PubMed:21412338, CC ECO:0000269|PubMed:21412339}. CC -!- ACTIVITY REGULATION: The CatSper calcium channel is indirectly CC activated by extracellular progesterone and prostaglandins following CC the sequence: progesterone > PGF1-alpha = PGE1 > PGA1 > PGE2 >> PGD2 CC (PubMed:21412338, PubMed:21412339, PubMed:26989199). The CatSper CC calcium channel is directly inhibited by endocannabinoid 2- CC arachidonoylglycerol (2AG) (PubMed:26989199). Indirect activation by CC progesterone takes place via the following mechanism: progesterone CC binds and activates the acylglycerol lipase ABHD2, which in turn CC mediates hydrolysis of 2AG inhibitor, relieving inhibition of the CC CatSper channel (PubMed:26989199). The primary effect of progesterone CC activation is to shift voltage dependence towards more physiological, CC negative membrane potentials; it is not mediated by metabotropic CC receptors and second messengers (PubMed:21412338, PubMed:21412339). CC Sperm capacitation enhances the effect of progesterone by providing CC additional negative shift. Also activated by the elevation of CC intracellular pH (PubMed:21412338, PubMed:21412339). CC {ECO:0000269|PubMed:21412338, ECO:0000269|PubMed:21412339, CC ECO:0000269|PubMed:26989199}. CC -!- SUBUNIT: Component of the CatSper complex or CatSpermasome composed of CC the core pore-forming members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 CC as well as auxiliary members CATSPERB, CATSPERG, CATSPERD, CATSPERE, CC CATSPERZ, C2CD6/CATSPERT, TMEM249, TMEM262 and EFCAB9 (By similarity). CC HSPA1 may be an additional auxiliary complex member (By similarity). CC The core complex members CATSPER1, CATSPER2, CATSPER3 and CATSPER4 form CC a heterotetrameric channel (By similarity). The auxiliary CATSPERB, CC CATSPERG, CATSPERD and CATSPERE subunits form a pavilion-like structure CC over the pore which stabilizes the complex through interactions with CC CATSPER4, CATSPER3, CATSPER1 and CATSPER2 respectively (By similarity). CC TMEM262/CATSPERH interacts with CATSPERB, further stabilizing the CC complex. C2CD6/CATSPERT interacts at least with CATSPERD and is CC required for targeting the CatSper complex in the flagellar membrane CC (By similarity). Interacts with Ca(v)3.3/CACNA1I, leading to CC suppression of T-type calcium channel activity (PubMed:16740636). CC {ECO:0000250|UniProtKB:A2ARP9, ECO:0000250|UniProtKB:Q91ZR5, CC ECO:0000269|PubMed:16740636}. CC -!- INTERACTION: CC Q96P56; Q9P0X4: CACNA1I; NbExp=3; IntAct=EBI-2215024, EBI-1220829; CC -!- SUBCELLULAR LOCATION: Cell projection, cilium, flagellum membrane CC {ECO:0000250|UniProtKB:A2ARP9}; Multi-pass membrane protein CC {ECO:0000250|UniProtKB:A2ARP9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=Variant 2; CC IsoId=Q96P56-1; Sequence=Displayed; CC Name=2; Synonyms=Variant 1; CC IsoId=Q96P56-2; Sequence=VSP_026976; CC Name=3; Synonyms=Variant 3; CC IsoId=Q96P56-3; Sequence=VSP_026975, VSP_026977; CC Name=4; CC IsoId=Q96P56-4; Sequence=VSP_026973, VSP_026974; CC -!- TISSUE SPECIFICITY: Testis-specific. {ECO:0000269|PubMed:11675491, CC ECO:0000269|PubMed:17347248}. CC -!- DISEASE: Deafness-infertility syndrome (DIS) [MIM:611102]: CC Characterized by deafness and infertility and is caused by large CC contiguous gene deletions at 15q15.3 that removes both STRC and CC CATSPER2 genes. {ECO:0000269|PubMed:12825070, CC ECO:0000269|PubMed:17098888}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the cation channel sperm-associated CC (TC 1.A.1.19) family. {ECO:0000305}. CC -!- CAUTION: In mouse, Slco6c1 is an additional auxiliary subunit of the CC CatSper complex. It is unclear if the related SLCO6A1 protein performs CC the same role in non-rodent species. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF411817; AAL26490.1; -; mRNA. DR EMBL; AF411818; AAL26491.1; -; mRNA. DR EMBL; AF411819; AAL26492.1; -; mRNA. DR EMBL; BC028728; AAH28728.1; -; mRNA. DR EMBL; BC064387; AAH64387.1; -; mRNA. DR CCDS; CCDS10099.1; -. [Q96P56-1] DR CCDS; CCDS32216.1; -. [Q96P56-2] DR RefSeq; NP_001269238.1; NM_001282309.1. [Q96P56-2] DR RefSeq; NP_473361.1; NM_054020.3. DR RefSeq; NP_742093.1; NM_172095.2. [Q96P56-1] DR RefSeq; XP_016877393.1; XM_017021904.1. DR AlphaFoldDB; Q96P56; -. DR SMR; Q96P56; -. DR BioGRID; 125561; 3. DR IntAct; Q96P56; 2. DR STRING; 9606.ENSP00000371180; -. DR DrugCentral; Q96P56; -. DR GuidetoPHARMACOLOGY; 389; -. DR TCDB; 1.A.1.19.2; the voltage-gated ion channel (vic) superfamily. DR iPTMnet; Q96P56; -. DR PhosphoSitePlus; Q96P56; -. DR BioMuta; CATSPER2; -. DR DMDM; 156631018; -. DR MassIVE; Q96P56; -. DR PaxDb; 9606-ENSP00000371180; -. DR PeptideAtlas; Q96P56; -. DR ProteomicsDB; 77633; -. [Q96P56-1] DR ProteomicsDB; 77634; -. [Q96P56-2] DR ProteomicsDB; 77635; -. [Q96P56-3] DR ProteomicsDB; 77636; -. [Q96P56-4] DR Antibodypedia; 11368; 147 antibodies from 17 providers. DR DNASU; 117155; -. DR Ensembl; ENST00000321596.6; ENSP00000321463.5; ENSG00000166762.19. [Q96P56-2] DR Ensembl; ENST00000396879.8; ENSP00000380088.3; ENSG00000166762.19. [Q96P56-1] DR Ensembl; ENST00000433380.5; ENSP00000389746.1; ENSG00000166762.19. [Q96P56-3] DR GeneID; 117155; -. DR KEGG; hsa:117155; -. DR MANE-Select; ENST00000396879.8; ENSP00000380088.3; NM_172095.4; NP_742093.1. DR UCSC; uc001zsh.5; human. [Q96P56-1] DR AGR; HGNC:18810; -. DR CTD; 117155; -. DR DisGeNET; 117155; -. DR GeneCards; CATSPER2; -. DR GeneReviews; CATSPER2; -. DR HGNC; HGNC:18810; CATSPER2. DR HPA; ENSG00000166762; Tissue enhanced (retina, testis). DR MalaCards; CATSPER2; -. DR MIM; 607249; gene. DR MIM; 611102; phenotype. DR neXtProt; NX_Q96P56; -. DR OpenTargets; ENSG00000166762; -. DR Orphanet; 94064; Deafness-infertility syndrome. DR PharmGKB; PA38691; -. DR VEuPathDB; HostDB:ENSG00000166762; -. DR eggNOG; KOG2301; Eukaryota. DR GeneTree; ENSGT00910000144338; -. DR HOGENOM; CLU_038828_0_0_1; -. DR InParanoid; Q96P56; -. DR OMA; QVVWPRD; -. DR OrthoDB; 5392781at2759; -. DR PhylomeDB; Q96P56; -. DR TreeFam; TF343585; -. DR PathwayCommons; Q96P56; -. DR Reactome; R-HSA-1300642; Sperm Motility And Taxes. DR SignaLink; Q96P56; -. DR BioGRID-ORCS; 117155; 7 hits in 1145 CRISPR screens. DR GeneWiki; CatSper2; -. DR GenomeRNAi; 117155; -. DR Pharos; Q96P56; Tchem. DR PRO; PR:Q96P56; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; Q96P56; Protein. DR Bgee; ENSG00000166762; Expressed in cerebellar vermis and 151 other cell types or tissues. DR ExpressionAtlas; Q96P56; baseline and differential. DR GO; GO:0036128; C:CatSper complex; ISS:UniProtKB. DR GO; GO:0031514; C:motile cilium; IEA:UniProtKB-KW. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005262; F:calcium channel activity; IEA:UniProtKB-KW. DR GO; GO:0005227; F:calcium-activated cation channel activity; IEA:InterPro. DR GO; GO:0009566; P:fertilization; IBA:GO_Central. DR GO; GO:0030317; P:flagellated sperm motility; IBA:GO_Central. DR GO; GO:0048240; P:sperm capacitation; IBA:GO_Central. DR Gene3D; 1.10.287.70; -; 1. DR Gene3D; 1.20.120.350; Voltage-gated potassium channels. Chain C; 1. DR InterPro; IPR028747; CatSper2. DR InterPro; IPR005821; Ion_trans_dom. DR InterPro; IPR027359; Volt_channel_dom_sf. DR PANTHER; PTHR46923; CATION CHANNEL SPERM-ASSOCIATED PROTEIN 2; 1. DR PANTHER; PTHR46923:SF1; CATION CHANNEL SPERM-ASSOCIATED PROTEIN 2; 1. DR Pfam; PF00520; Ion_trans; 1. DR SUPFAM; SSF81324; Voltage-gated potassium channels; 1. DR Genevisible; Q96P56; HS. PE 1: Evidence at protein level; KW Alternative splicing; Calcium; Calcium channel; Calcium transport; KW Cell membrane; Cell projection; Cilium; Developmental protein; KW Differentiation; Flagellum; Ion channel; Ion transport; Membrane; KW Reference proteome; Spermatogenesis; Transmembrane; Transmembrane helix; KW Transport; Voltage-gated channel. FT CHAIN 1..530 FT /note="Cation channel sperm-associated protein 2" FT /id="PRO_0000295676" FT TOPO_DOM 1..108 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 109..131 FT /note="Helical; Name=Segment S1" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 132..140 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 141..166 FT /note="Helical; Name=Segment S2" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 167..175 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 176..200 FT /note="Helical; Name=Segment S3" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 201..203 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 204..222 FT /note="Helical; Name=Segment S4" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 223..239 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 240..262 FT /note="Helical; Name=Segment S5" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 263..281 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT INTRAMEM 282..294 FT /note="Helical; Pore-forming" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 295..314 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TRANSMEM 315..341 FT /note="Helical; Name=Segment S6" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT TOPO_DOM 342..530 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:A2ARP9" FT REGION 378..458 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 378..398 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 399..424 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 439..458 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT VAR_SEQ 188..199 FT /note="SLLPEVVVLVGV -> VRIEILRVRLVG (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_026973" FT VAR_SEQ 200..530 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_026974" FT VAR_SEQ 393..414 FT /note="SSRGASQQRESLDLSEVSEVES -> RSFGLGDSCARKSARANGNGSG (in FT isoform 3)" FT /evidence="ECO:0000303|PubMed:11675491" FT /id="VSP_026975" FT VAR_SEQ 393..394 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:11675491, FT ECO:0000303|PubMed:15489334" FT /id="VSP_026976" FT VAR_SEQ 415..530 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:11675491" FT /id="VSP_026977" FT VARIANT 8 FT /note="E -> G (in dbSNP:rs2614835)" FT /id="VAR_033307" FT VARIANT 57 FT /note="V -> I (in dbSNP:rs8042868)" FT /id="VAR_033308" FT CONFLICT 46 FT /note="E -> K (in Ref. 2; AAH28728)" FT /evidence="ECO:0000305" SQ SEQUENCE 530 AA; 62041 MW; 8561CC0E9F3590B0 CRC64; MAAYQQEEQM QLPRADAIRS RLIDTFSLIE HLQGLSQAVP RHTIRELLDP SRQKKLVLGD QHQLVRFSIK PQRIEQISHA QRLLSRLHVR CSQRPPLSLW AGWVLECPLF KNFIIFLVFL NTIILMVEIE LLESTNTKLW PLKLTLEVAA WFILLIFILE ILLKWLSNFS VFWKSAWNVF DFVVTMLSLL PEVVVLVGVT GQSVWLQLLR ICRVLRSLKL LAQFRQIQII ILVLVRALKS MTFLLMLLLI FFYIFAVTGV YVFSEYTRSP RQDLEYHVFF SDLPNSLVTV FILFTLDHWY ALLQDVWKVP EVSRIFSSIY FILWLLLGSI IFRSIIVAMM VTNFQNIRKE LNEEMARREV QLKADMFKRQ IIQRRKNMSH EALTSSHSKI EDSSRGASQQ RESLDLSEVS EVESNYGATE EDLITSASKT EETLSKKREY QSSSCVSSTS SSYSSSSESR FSESIGRLDW ETLVHENLPG LMEMDQDDRV WPRDSLFRYF ELLEKLQYNL EERKKLQEFA VQALMNLEDK //