ID PCSK4_HUMAN Reviewed; 755 AA. AC Q6UW60; Q8IY88; Q9UF79; DT 25-JUL-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 2. DT 27-MAR-2024, entry version 158. DE RecName: Full=Proprotein convertase subtilisin/kexin type 4; DE EC=3.4.21.-; DE AltName: Full=Proprotein convertase 4; DE Short=PC4; DE Flags: Precursor; GN Name=PCSK4 {ECO:0000312|EMBL:AAH36354.1}; GN Synonyms=PC4 {ECO:0000303|PubMed:16040806}; ORFNames=UNQ2757/PRO6496; 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] {ECO:0000305, ECO:0000312|EMBL:AAQ89322.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=12975309; DOI=10.1101/gr.1293003; RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A., RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.; RT "The secreted protein discovery initiative (SPDI), a large-scale effort to RT identify novel human secreted and transmembrane proteins: a bioinformatics RT assessment."; RL Genome Res. 13:2265-2270(2003). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [3] {ECO:0000305, ECO:0000312|EMBL:AAH36354.1} RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Brain {ECO:0000312|EMBL:AAH36354.1}; 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 [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 526-755 (ISOFORMS 1/2). RC TISSUE=Testis; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [5] {ECO:0000305} RP FUNCTION, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=16040806; DOI=10.1073/pnas.0502357102; RA Qiu Q., Basak A., Mbikay M., Tsang B.K., Gruslin A.; RT "Role of pro-IGF-II processing by proprotein convertase 4 in human RT placental development."; RL Proc. Natl. Acad. Sci. U.S.A. 102:11047-11052(2005). RN [6] RP GLYCOSYLATION, MUTAGENESIS OF SER-373, INTERACTION WITH HSPA5, AND RP PROTEOLYTIC CLEAVAGE. RX PubMed=21080038; DOI=10.1007/s11010-010-0635-y; RA Gyamera-Acheampong C., Sirois F., Denis N.J., Mishra P., Figeys D., RA Basak A., Mbikay M.; RT "The precursor to the germ cell-specific PCSK4 proteinase is inefficiently RT activated in transfected somatic cells: evidence of interaction with the RT BiP chaperone."; RL Mol. Cell. Biochem. 348:43-52(2011). CC -!- FUNCTION: Proprotein convertase involved in the processing of hormone CC and other protein precursors at sites comprised of pairs of basic amino CC acid residues (By similarity). In males, important for ADAM2 processing CC as well as other acrosomal proteins with roles in fertilization and CC critical for normal fertilization events such as sperm capacitation, CC acrosome reaction and binding of sperm to zona pellucida (By CC similarity). Also plays a role in female fertility, involved in the CC regulation of trophoblast migration and placental development, may be CC through the proteolytical processing and activation of proteins such as CC IGF2 (PubMed:16040806). May also participate in folliculogenesis in the CC ovaries (By similarity). {ECO:0000250|UniProtKB:P29121, CC ECO:0000269|PubMed:16040806}. CC -!- SUBUNIT: The proPCSK4 form interacts with HSPA5; the interaction takes CC place at the endoplasmic reticulum. {ECO:0000269|PubMed:21080038}. CC -!- INTERACTION: CC Q6UW60; Q12797-6: ASPH; NbExp=3; IntAct=EBI-13342757, EBI-12092171; CC Q6UW60-2; P42858: HTT; NbExp=3; IntAct=EBI-25960845, EBI-466029; CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane CC protein {ECO:0000255}. Cytoplasmic vesicle, secretory vesicle, acrosome CC membrane {ECO:0000250|UniProtKB:P29121}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1 {ECO:0000269|PubMed:12975309}; CC IsoId=Q6UW60-1; Sequence=Displayed; CC Name=2 {ECO:0000269|PubMed:15489334}; CC IsoId=Q6UW60-2; Sequence=VSP_052097; CC -!- TISSUE SPECIFICITY: Placenta. {ECO:0000269|PubMed:16040806}. CC -!- DEVELOPMENTAL STAGE: Localized predominantly in the cytotrophoblast CC layer of trophoblast cells during the first trimester of pregnancy, and CC to the syncytiotrophoblast and stroma cells during the third trimester. CC {ECO:0000269|PubMed:16040806}. CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:21080038}. CC -!- PTM: Synthesized in the endoplasmic reticulum as a zymogen, is matured CC by autocatalytic cleavage between the prodomain and the catalytic CC domain. {ECO:0000305|PubMed:21080038}. CC -!- SIMILARITY: Belongs to the peptidase S8 family. Furin subfamily. CC {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; AY358963; AAQ89322.1; -; mRNA. DR EMBL; AC027307; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC036354; AAH36354.1; -; mRNA. DR EMBL; AL133566; CAB63719.3; -; mRNA. DR CCDS; CCDS12069.2; -. [Q6UW60-1] DR PIR; T43487; T43487. DR RefSeq; NP_060043.2; NM_017573.4. [Q6UW60-1] DR AlphaFoldDB; Q6UW60; -. DR SMR; Q6UW60; -. DR BioGRID; 120136; 4. DR CORUM; Q6UW60; -. DR IntAct; Q6UW60; 3. DR STRING; 9606.ENSP00000300954; -. DR BindingDB; Q6UW60; -. DR ChEMBL; CHEMBL4861; -. DR GuidetoPHARMACOLOGY; 2384; -. DR MEROPS; S08.074; -. DR GlyCosmos; Q6UW60; 2 sites, No reported glycans. DR GlyGen; Q6UW60; 2 sites. DR iPTMnet; Q6UW60; -. DR PhosphoSitePlus; Q6UW60; -. DR BioMuta; PCSK4; -. DR DMDM; 296439263; -. DR MassIVE; Q6UW60; -. DR PaxDb; 9606-ENSP00000300954; -. DR PeptideAtlas; Q6UW60; -. DR ProteomicsDB; 67450; -. [Q6UW60-1] DR Antibodypedia; 1614; 177 antibodies from 25 providers. DR DNASU; 54760; -. DR Ensembl; ENST00000300954.10; ENSP00000300954.5; ENSG00000115257.15. [Q6UW60-1] DR GeneID; 54760; -. DR KEGG; hsa:54760; -. DR MANE-Select; ENST00000300954.10; ENSP00000300954.5; NM_017573.5; NP_060043.2. DR UCSC; uc002ltb.3; human. [Q6UW60-1] DR AGR; HGNC:8746; -. DR CTD; 54760; -. DR DisGeNET; 54760; -. DR GeneCards; PCSK4; -. DR HGNC; HGNC:8746; PCSK4. DR HPA; ENSG00000115257; Tissue enriched (testis). DR MIM; 600487; gene. DR neXtProt; NX_Q6UW60; -. DR OpenTargets; ENSG00000115257; -. DR PharmGKB; PA33092; -. DR VEuPathDB; HostDB:ENSG00000115257; -. DR eggNOG; KOG3525; Eukaryota. DR GeneTree; ENSGT00940000161989; -. DR HOGENOM; CLU_002976_4_0_1; -. DR InParanoid; Q6UW60; -. DR OMA; PQKKCAI; -. DR OrthoDB; 5474719at2759; -. DR PhylomeDB; Q6UW60; -. DR TreeFam; TF314277; -. DR BRENDA; 3.4.21.B24; 2681. DR BRENDA; 3.4.21.B25; 2681. DR PathwayCommons; Q6UW60; -. DR SignaLink; Q6UW60; -. DR BioGRID-ORCS; 54760; 10 hits in 1158 CRISPR screens. DR ChiTaRS; PCSK4; human. DR GeneWiki; PCSK4; -. DR GenomeRNAi; 54760; -. DR Pharos; Q6UW60; Tbio. DR PRO; PR:Q6UW60; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q6UW60; Protein. DR Bgee; ENSG00000115257; Expressed in left testis and 94 other cell types or tissues. DR ExpressionAtlas; Q6UW60; baseline and differential. DR GO; GO:0002080; C:acrosomal membrane; ISS:UniProtKB. DR GO; GO:0001669; C:acrosomal vesicle; ISS:UniProtKB. DR GO; GO:0016020; C:membrane; IBA:GO_Central. DR GO; GO:0005802; C:trans-Golgi network; IBA:GO_Central. DR GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central. DR GO; GO:0007340; P:acrosome reaction; ISS:UniProtKB. DR GO; GO:0007339; P:binding of sperm to zona pellucida; ISS:UniProtKB. DR GO; GO:0009566; P:fertilization; ISS:UniProtKB. DR GO; GO:0016486; P:peptide hormone processing; IBA:GO_Central. DR GO; GO:0016485; P:protein processing; IDA:UniProtKB. DR GO; GO:0022414; P:reproductive process; ISS:UniProtKB. DR GO; GO:0048240; P:sperm capacitation; ISS:UniProtKB. DR CDD; cd00064; FU; 1. DR CDD; cd04059; Peptidases_S8_Protein_convertases_Kexins_Furin-like; 1. DR Gene3D; 2.60.120.260; Galactose-binding domain-like; 1. DR Gene3D; 3.30.70.850; Peptidase S8, pro-domain; 1. DR Gene3D; 3.40.50.200; Peptidase S8/S53 domain; 1. DR InterPro; IPR006212; Furin_repeat. DR InterPro; IPR008979; Galactose-bd-like_sf. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR034182; Kexin/furin. DR InterPro; IPR002884; P_dom. DR InterPro; IPR000209; Peptidase_S8/S53_dom. DR InterPro; IPR036852; Peptidase_S8/S53_dom_sf. DR InterPro; IPR023827; Peptidase_S8_Asp-AS. DR InterPro; IPR022398; Peptidase_S8_His-AS. DR InterPro; IPR023828; Peptidase_S8_Ser-AS. DR InterPro; IPR015500; Peptidase_S8_subtilisin-rel. DR InterPro; IPR032815; S8_pro-domain. DR InterPro; IPR038466; S8_pro-domain_sf. DR PANTHER; PTHR42884; PROPROTEIN CONVERTASE SUBTILISIN/KEXIN-RELATED; 1. DR PANTHER; PTHR42884:SF16; PROPROTEIN CONVERTASE SUBTILISIN_KEXIN TYPE 4; 1. DR Pfam; PF01483; P_proprotein; 1. DR Pfam; PF00082; Peptidase_S8; 1. DR Pfam; PF16470; S8_pro-domain; 1. DR PRINTS; PR00723; SUBTILISIN. DR SMART; SM00261; FU; 1. DR SUPFAM; SSF49785; Galactose-binding domain-like; 1. DR SUPFAM; SSF57184; Growth factor receptor domain; 1. DR SUPFAM; SSF54897; Protease propeptides/inhibitors; 1. DR SUPFAM; SSF52743; Subtilisin-like; 1. DR PROSITE; PS51829; P_HOMO_B; 1. DR PROSITE; PS51892; SUBTILASE; 1. DR PROSITE; PS00136; SUBTILASE_ASP; 1. DR PROSITE; PS00137; SUBTILASE_HIS; 1. DR PROSITE; PS00138; SUBTILASE_SER; 1. DR Genevisible; Q6UW60; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cleavage on pair of basic residues; KW Cytoplasmic vesicle; Glycoprotein; Hydrolase; Membrane; Protease; KW Reference proteome; Serine protease; Signal; Transmembrane; KW Transmembrane helix; Zymogen. FT SIGNAL 1..25 FT /evidence="ECO:0000255" FT PROPEP 26..113 FT /evidence="ECO:0000250|UniProtKB:P29121, ECO:0000255" FT /id="PRO_0000246778" FT CHAIN 114..755 FT /note="Proprotein convertase subtilisin/kexin type 4" FT /evidence="ECO:0000250|UniProtKB:P29121, ECO:0000255" FT /id="PRO_0000246779" FT TRANSMEM 709..729 FT /note="Helical" FT /evidence="ECO:0000255" FT DOMAIN 126..440 FT /note="Peptidase S8" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT DOMAIN 449..581 FT /note="P/Homo B" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01173" FT ACT_SITE 158 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 199 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT ACT_SITE 373 FT /note="Charge relay system" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240" FT CARBOHYD 475 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 629 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 1..513 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334" FT /id="VSP_052097" FT VARIANT 267 FT /note="T -> M (in dbSNP:rs36123574)" FT /id="VAR_061772" FT MUTAGEN 373 FT /note="S->A: No effect on interaction with HSPA5." FT /evidence="ECO:0000269|PubMed:21080038" FT CONFLICT 66 FT /note="P -> S (in Ref. 1; AAQ89322 and 3; AAH36354)" FT /evidence="ECO:0000305" SQ SEQUENCE 755 AA; 82795 MW; 29E9D2CD579C1CEF CRC64; MRPAPIALWL RLVLALALVR PRAVGWAPVR APIYVSSWAV QVSQGNREVE RLARKFGFVN LGPIFPDGQY FHLRHRGVVQ QSLTPHWGHR LHLKKNPKVQ WFQQQTLQRR VKRSVVVPTD PWFSKQWYMN SEAQPDLSIL QAWSQGLSGQ GIVVSVLDDG IEKDHPDLWA NYDPLASYDF NDYDPDPQPR YTPSKENRHG TRCAGEVAAM ANNGFCGVGV AFNARIGGVR MLDGTITDVI EAQSLSLQPQ HIHIYSASWG PEDDGRTVDG PGILTREAFR RGVTKGRGGL GTLFIWASGN GGLHYDNCNC DGYTNSIHTL SVGSTTQQGR VPWYSEACAS TLTTTYSSGV ATDPQIVTTD LHHGCTDQHT GTSASAPLAA GMIALALEAN PFLTWRDMQH LVVRASKPAH LQAEDWRTNG VGRQVSHHYG YGLLDAGLLV DTARTWLPTQ PQRKCAVRVQ SRPTPILPLI YIRENVSACA GLHNSIRSLE HVQAQLTLSY SRRGDLEISL TSPMGTRSTL VAIRPLDVST EGYNNWVFMS THFWDENPQG VWTLGLENKG YYFNTGTLYR YTLLLYGTAE DMTARPTGPQ VTSSACVQRD TEGLCQACDG PAYILGQLCL AYCPPRFFNH TRLVTAGPGH TAAPALRVCS SCHASCYTCR GGSPRDCTSC PPSSTLDQQQ GSCMGPTTPD SRPRLRAAAC PHHRCPASAM VLSLLAVTLG GPVLCGMSMD LPLYAWLSRA RATPTKPQVW LPAGT //