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PCSK4_HUMAN
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   03-AUG-2022, entry version 150.
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}.
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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; 3.
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   GlyGen; Q6UW60; 2 sites.
DR   iPTMnet; Q6UW60; -.
DR   PhosphoSitePlus; Q6UW60; -.
DR   BioMuta; PCSK4; -.
DR   DMDM; 296439263; -.
DR   MassIVE; Q6UW60; -.
DR   PaxDb; Q6UW60; -.
DR   PeptideAtlas; Q6UW60; -.
DR   PRIDE; Q6UW60; -.
DR   Antibodypedia; 1614; 156 antibodies from 24 providers.
DR   DNASU; 54760; -.
DR   Ensembl; ENST00000300954.9; 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   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; ENPQGLW; -.
DR   OrthoDB; 473018at2759; -.
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 1080 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 92 other tissues.
DR   ExpressionAtlas; Q6UW60; baseline and differential.
DR   Genevisible; Q6UW60; HS.
DR   GO; GO:0002080; C:acrosomal membrane; ISS:UniProtKB.
DR   GO; GO:0001669; C:acrosomal vesicle; ISS:UniProtKB.
DR   GO; GO:0030173; C:integral component of Golgi membrane; IBA:GO_Central.
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; 3.30.70.850; -; 1.
DR   Gene3D; 3.40.50.200; -; 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   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; SSF49785; 1.
DR   SUPFAM; SSF52743; SSF52743; 1.
DR   SUPFAM; SSF57184; SSF57184; 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.
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
 
 
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