CTSR4_HUMAN
ID CTSR4_HUMAN Reviewed; 472 AA.
AC Q7RTX7; A1A4W6; Q5VY71;
DT 24-JUL-2007, integrated into UniProtKB/Swiss-Prot.
DT 15-DEC-2003, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Cation channel sperm-associated protein 4;
DE Short=CatSper4;
GN Name=CATSPER4;
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 [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
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 IDENTIFICATION, AND TISSUE SPECIFICITY.
RX PubMed=12932298; DOI=10.1186/1477-7827-1-53;
RA Lobley A., Pierron V., Reynolds L., Allen L., Michalovich D.;
RT "Identification of human and mouse CatSper3 and CatSper4 genes:
RT characterisation of a common interaction domain and evidence for expression
RT in testis.";
RL Reprod. Biol. Endocrinol. 1:53-53(2003).
RN [4]
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 [5]
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 [6]
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 [7]
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. The auxiliary CATSPERB, CATSPERG, CATSPERD
CC and CATSPERE subunits form a pavilion-like structure over the pore
CC which stabilizes the complex through interactions with CATSPER4,
CC 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). {ECO:0000250|UniProtKB:Q8BVN3,
CC ECO:0000250|UniProtKB:Q91ZR5}.
CC -!- INTERACTION:
CC Q7RTX7; Q8NHW4: CCL4L2; NbExp=3; IntAct=EBI-21541251, EBI-10271156;
CC -!- SUBCELLULAR LOCATION: Cell projection, cilium, flagellum membrane
CC {ECO:0000250|UniProtKB:Q8BVN3}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q8BVN3}. Note=Specifically located in the
CC principal piece of the sperm tail. {ECO:0000250|UniProtKB:Q8BVN3}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q7RTX7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q7RTX7-2; Sequence=VSP_026979, VSP_026980;
CC -!- TISSUE SPECIFICITY: Testis-specific. {ECO:0000269|PubMed:12932298,
CC ECO:0000269|PubMed:17347248}.
CC -!- SIMILARITY: Belongs to the cation channel sperm-associated (TC
CC 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 -!- SEQUENCE CAUTION:
CC Sequence=AAI28139.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; AL355877; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC128138; AAI28139.1; ALT_FRAME; mRNA.
DR EMBL; BC128139; AAI28140.1; -; mRNA.
DR EMBL; BN000273; CAE30475.1; -; mRNA.
DR CCDS; CCDS30645.1; -. [Q7RTX7-1]
DR RefSeq; NP_937770.1; NM_198137.1. [Q7RTX7-1]
DR AlphaFoldDB; Q7RTX7; -.
DR SMR; Q7RTX7; -.
DR BioGRID; 132049; 13.
DR IntAct; Q7RTX7; 5.
DR STRING; 9606.ENSP00000390423; -.
DR DrugCentral; Q7RTX7; -.
DR GuidetoPHARMACOLOGY; 391; -.
DR TCDB; 1.A.1.19.1; the voltage-gated ion channel (vic) superfamily.
DR iPTMnet; Q7RTX7; -.
DR PhosphoSitePlus; Q7RTX7; -.
DR BioMuta; CATSPER4; -.
DR DMDM; 74713153; -.
DR MassIVE; Q7RTX7; -.
DR PaxDb; Q7RTX7; -.
DR PeptideAtlas; Q7RTX7; -.
DR PRIDE; Q7RTX7; -.
DR Antibodypedia; 51012; 94 antibodies from 21 providers.
DR DNASU; 378807; -.
DR Ensembl; ENST00000456354.7; ENSP00000390423.3; ENSG00000188782.9. [Q7RTX7-1]
DR Ensembl; ENST00000518899.5; ENSP00000429464.1; ENSG00000188782.9. [Q7RTX7-2]
DR GeneID; 378807; -.
DR KEGG; hsa:378807; -.
DR MANE-Select; ENST00000456354.7; ENSP00000390423.3; NM_198137.2; NP_937770.1.
DR UCSC; uc009vsf.4; human. [Q7RTX7-1]
DR CTD; 378807; -.
DR DisGeNET; 378807; -.
DR GeneCards; CATSPER4; -.
DR HGNC; HGNC:23220; CATSPER4.
DR HPA; ENSG00000188782; Tissue enriched (testis).
DR MIM; 609121; gene.
DR neXtProt; NX_Q7RTX7; -.
DR OpenTargets; ENSG00000188782; -.
DR PharmGKB; PA134941696; -.
DR VEuPathDB; HostDB:ENSG00000188782; -.
DR eggNOG; KOG2301; Eukaryota.
DR GeneTree; ENSGT00940000161879; -.
DR InParanoid; Q7RTX7; -.
DR OMA; NRRDITS; -.
DR OrthoDB; 1270192at2759; -.
DR PhylomeDB; Q7RTX7; -.
DR TreeFam; TF343841; -.
DR PathwayCommons; Q7RTX7; -.
DR Reactome; R-HSA-1300642; Sperm Motility And Taxes.
DR SignaLink; Q7RTX7; -.
DR BioGRID-ORCS; 378807; 8 hits in 1060 CRISPR screens.
DR GeneWiki; CatSper4; -.
DR GenomeRNAi; 378807; -.
DR Pharos; Q7RTX7; Tchem.
DR PRO; PR:Q7RTX7; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; Q7RTX7; protein.
DR Bgee; ENSG00000188782; Expressed in left testis and 10 other tissues.
DR ExpressionAtlas; Q7RTX7; baseline and differential.
DR GO; GO:0001669; C:acrosomal vesicle; IBA:GO_Central.
DR GO; GO:0036128; C:CatSper complex; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0097228; C:sperm principal piece; ISS:UniProtKB.
DR GO; GO:0005227; F:calcium activated cation channel activity; IEA:InterPro.
DR GO; GO:0005245; F:voltage-gated calcium channel activity; IBA:GO_Central.
DR GO; GO:0051649; P:establishment of localization in cell; IEA:Ensembl.
DR GO; GO:0030317; P:flagellated sperm motility; IBA:GO_Central.
DR GO; GO:0034765; P:regulation of ion transmembrane transport; IEA:UniProtKB-KW.
DR GO; GO:0006814; P:sodium ion transport; IBA:GO_Central.
DR GO; GO:0048240; P:sperm capacitation; IBA:GO_Central.
DR Gene3D; 1.20.120.350; -; 1.
DR InterPro; IPR028744; CatSper4.
DR InterPro; IPR005821; Ion_trans_dom.
DR InterPro; IPR027359; Volt_channel_dom_sf.
DR PANTHER; PTHR47077; PTHR47077; 1.
DR Pfam; PF00520; Ion_trans; 1.
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..472
FT /note="Cation channel sperm-associated protein 4"
FT /id="PRO_0000295681"
FT TOPO_DOM 1..90
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 91..112
FT /note="Helical; Name=Segment S1"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 113..122
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 123..149
FT /note="Helical; Name=Segment S2"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 150..153
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 154..177
FT /note="Helical; Name=Segment S3"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 178..180
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 181..199
FT /note="Helical; Name=Segment S4"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 200..212
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 213..236
FT /note="Helical; Name=Segment S5"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 237..246
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT INTRAMEM 247..258
FT /note="Helical; Pore-forming"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 259..279
FT /note="Extracellular"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TRANSMEM 280..307
FT /note="Helical; Name=Segment S6"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT TOPO_DOM 308..472
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:Q8BVN3"
FT REGION 416..438
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 227..242
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026979"
FT VAR_SEQ 401..472
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_026980"
FT VARIANT 77
FT /note="Q -> R (in dbSNP:rs11247866)"
FT /id="VAR_033310"
FT VARIANT 124
FT /note="L -> F (in dbSNP:rs12138368)"
FT /id="VAR_033311"
FT VARIANT 293
FT /note="I -> V (in dbSNP:rs17257155)"
FT /id="VAR_033312"
FT VARIANT 436
FT /note="D -> N (in dbSNP:rs6657616)"
FT /id="VAR_033313"
SQ SEQUENCE 472 AA; 54092 MW; 5AC94CD0971A25FE CRC64;
MRDNEKAWWQ QWTSHTGLEG WGGTQEDRMG FGGAVAALRG RPSPLQSTIH ESYGRPEEQV
LINRQEITNK ADAWDMQEFI THMYIKQLLR HPAFQLLLAL LLVINAITIA LRTNSYLDQK
HYELFSTIDD IVLTILLCEV LLGWLNGFWI FWKDGWNILN FIIVFILLLR FFINEINIPS
INYTLRALRL VHVCMAVEPL ARIIRVILQS VPDMANIMVL ILFFMLVFSV FGVTLFGAFV
PKHFQNIQVA LYTLFICITQ DGWVDIYSDF QTEKREYAME IGGAIYFTIF ITIGAFIGIN
LFVIVVTTNL EQMMKAGEQG QQQRITFSET GAEEEEENDQ LPLVHCVVAR SEKSGLLQEP
LAGGPLSNLS ENTCDNFCLV LEAIQENLRQ YKEIRDELNM IVEEVRAIRF NQEQESEVLN
RRSSTSGSLE TTSSKDIRQM SQQQDLLSAL VSMEKVHDSS SQILLKKHKS SH
