PCSK4_MOUSE
ID PCSK4_MOUSE Reviewed; 655 AA.
AC P29121; Q62094;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 1.
DT 03-AUG-2022, entry version 170.
DE RecName: Full=Proprotein convertase subtilisin/kexin type 4;
DE EC=3.4.21.-;
DE AltName: Full=KEX2-like endoprotease 3;
DE AltName: Full=Neuroendocrine convertase 3;
DE Short=NEC 3;
DE AltName: Full=Prohormone convertase 3;
DE Flags: Precursor;
GN Name=Pcsk4; Synonyms=Nec-3, Nec3;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND
RP DEVELOPMENTAL STAGE.
RC TISSUE=Testis;
RX PubMed=1372895; DOI=10.1016/s0021-9258(18)42638-5;
RA Nakayama K., Kim W.-S., Torii S., Hosaka M., Nakagawa T., Ikemizu J.,
RA Baba T., Murakami K.;
RT "Identification of the fourth member of the mammalian endoprotease family
RT homologous to the yeast Kex2 protease. Its testis-specific expression.";
RL J. Biol. Chem. 267:5897-5900(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 3 AND 4).
RC TISSUE=Testis;
RX PubMed=1448111; DOI=10.1210/mend.6.10.1448111;
RA Seidah N.G., Day R., Hamelin J., Gaspar A., Collard M.W., Chretien M.;
RT "Testicular expression of PC4 in the rat: molecular diversity of a novel
RT germ cell-specific Kex2/subtilisin-like proprotein convertase.";
RL Mol. Endocrinol. 6:1559-1570(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1; 2; 5; 6; 7 AND 8).
RC STRAIN=C57BL/6J; TISSUE=Liver;
RX PubMed=8020970; DOI=10.1006/geno.1994.1158;
RA Mbikay M., Raffin-Sanson M.-L., Tadros H., Sirois F., Seidah N.G.,
RA Chretien M.;
RT "Structure of the gene for the testis-specific proprotein convertase 4 and
RT of its alternate messenger RNA isoforms.";
RL Genomics 20:231-237(1994).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9192653; DOI=10.1073/pnas.94.13.6842;
RA Mbikay M., Tadros H., Ishida N., Lerner C.P., De Lamirande E., Chen A.,
RA El-Alfy M., Clermont Y., Seidah N.G., Chretien M., Gagnon C., Simpson E.M.;
RT "Impaired fertility in mice deficient for the testicular germ-cell protease
RT PC4.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:6842-6846(1997).
RN [5]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=11164898; DOI=10.1016/s0165-0378(00)00085-1;
RA Tadros H., Chretien M., Mbikay M.;
RT "The testicular germ-cell protease PC4 is also expressed in macrophage-like
RT cells of the ovary.";
RL J. Reprod. Immunol. 49:133-152(2001).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=16371590; DOI=10.1095/biolreprod.105.046821;
RA Gyamera-Acheampong C., Tantibhedhyangkul J., Weerachatyanukul W.,
RA Tadros H., Xu H., van de Loo J.W., Pelletier R.M., Tanphaichitr N.,
RA Mbikay M.;
RT "Sperm from mice genetically deficient for the PCSK4 proteinase exhibit
RT accelerated capacitation, precocious acrosome reaction, reduced binding to
RT egg zona pellucida, and impaired fertilizing ability.";
RL Biol. Reprod. 74:666-673(2006).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=19342015; DOI=10.1016/j.fertnstert.2008.12.013;
RA Gyamera-Acheampong C., Vasilescu J., Figeys D., Mbikay M.;
RT "PCSK4-null sperm display enhanced protein tyrosine phosphorylation and
RT ADAM2 proteolytic processing during in vitro capacitation.";
RL Fertil. Steril. 93:1112-1123(2010).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=21302280; DOI=10.1002/jcp.22626;
RA Iamsaard S., Vanichviriyakit R., Hommalai G., Saewu A., Srakaew N.,
RA Withyachumnarnkul B., Basak A., Tanphaichitr N.;
RT "Enzymatic activity of sperm proprotein convertase is important for
RT mammalian fertilization.";
RL J. Cell. Physiol. 226:2817-2826(2011).
RN [9]
RP SUBCELLULAR LOCATION.
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).
RN [10]
RP DISRUPTION PHENOTYPE.
RX PubMed=22357636; DOI=10.1093/molehr/gas009;
RA Tardif S., Guyonnet B., Cormier N., Cornwall G.A.;
RT "Alteration in the processing of the ACRBP/sp32 protein and sperm
RT head/acrosome malformations in proprotein convertase 4 (PCSK4) null mice.";
RL Mol. Hum. Reprod. 18:298-307(2012).
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. In males, important for ADAM2 processing as well as
CC other acrosomal proteins with roles in fertilization and critical for
CC normal fertilization events such as sperm capacitation, acrosome
CC reaction and binding of sperm to zona pellucida (PubMed:9192653,
CC PubMed:16371590, PubMed:19342015, PubMed:21302280). Also plays a role
CC in female fertility, involved in the regulation of trophoblast
CC migration and placental development, may be through the proteolytical
CC processing and activation of proteins such as IGF2 (By similarity). May
CC also participate in folliculogenesis in the ovaries (PubMed:11164898).
CC {ECO:0000250|UniProtKB:Q6UW60, ECO:0000269|PubMed:11164898,
CC ECO:0000269|PubMed:16371590, ECO:0000269|PubMed:19342015,
CC ECO:0000269|PubMed:21302280, ECO:0000269|PubMed:9192653}.
CC -!- SUBUNIT: The proPCSK4 form interacts with HSPA5; the interaction takes
CC place at the endoplasmic reticulum. {ECO:0000250|UniProtKB:Q6UW60}.
CC -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle, acrosome
CC membrane {ECO:0000269|PubMed:16371590, ECO:0000269|PubMed:21080038,
CC ECO:0000269|PubMed:21302280}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=8;
CC Name=1; Synonyms=mPC4-A;
CC IsoId=P29121-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P29121-2; Sequence=VSP_011268;
CC Name=3; Synonyms=mPC4-B;
CC IsoId=P29121-3; Sequence=VSP_011271;
CC Name=4; Synonyms=mPC4-C;
CC IsoId=P29121-4; Sequence=VSP_011272;
CC Name=5; Synonyms=E;
CC IsoId=P29121-5; Sequence=VSP_011266;
CC Name=6; Synonyms=D;
CC IsoId=P29121-6; Sequence=VSP_011267;
CC Name=7; Synonyms=B;
CC IsoId=P29121-7; Sequence=VSP_011269;
CC Name=8; Synonyms=C;
CC IsoId=P29121-8; Sequence=VSP_011270;
CC -!- TISSUE SPECIFICITY: Expressed abundantly in the testis since postnatal
CC Day 16 (PubMed:1372895, PubMed:16371590, PubMed:21302280). In testis,
CC strongly detected in round and elongated spermatids as well as
CC spermatocytes. Also observed in residual bodies engulfed by Sertoli
CC cells at spermatogenic stages VIII and IX (PubMed:16371590). In
CC ovaries, expressed in macrophage-like cells of the ovarian theca,
CC interstitium and corpora lutea (PubMed:11164898).
CC {ECO:0000269|PubMed:11164898, ECO:0000269|PubMed:1372895,
CC ECO:0000269|PubMed:16371590, ECO:0000269|PubMed:21302280}.
CC -!- DEVELOPMENTAL STAGE: Detected only after the 20th day of postnatal
CC development. Mainly expressed in the round spermatids. Expressed mainly
CC in the early stages of spermiogenesis. {ECO:0000269|PubMed:1372895}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:Q6UW60}.
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:0000250|UniProtKB:Q6UW60}.
CC -!- DISRUPTION PHENOTYPE: Knockout males show impaired fertility
CC (PubMed:9192653). Sperm from mutants exhibit accelerated capacitation,
CC precocious acrosome reaction, reduced binding to egg zona pellucida,
CC and impaired fertilizing ability (PubMed:16371590). They have abnormal
CC acrosome formation during spermatogenesis (PubMed:22357636). Sperm
CC proteins are hyper-tyrosine phosphorylated during capacitation
CC (PubMed:19342015). In females, the percent of successful mating is
CC comparable to that of their PCSK4 +/- female littermates, however the
CC average litter size of the former is half that of the latter. Knockout
CC ovaries treated with gonatropin are generally smaller, less hyperemic
CC and with fewer corpora lutea than wild type. This difference is
CC associated with a 20-fold lower level of circulating progesterone
CC (PubMed:9192653). {ECO:0000269|PubMed:16371590,
CC ECO:0000269|PubMed:19342015, ECO:0000269|PubMed:22357636,
CC ECO:0000269|PubMed:9192653}.
CC -!- SIMILARITY: Belongs to the peptidase S8 family. Furin subfamily.
CC {ECO:0000305}.
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DR EMBL; D01093; BAA00877.1; -; mRNA.
DR EMBL; L21221; AAA39973.1; -; Genomic_DNA.
DR EMBL; L21210; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21211; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21212; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21213; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21214; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21215; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21216; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21217; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21218; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21219; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21220; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21222; AAA39973.1; JOINED; Genomic_DNA.
DR EMBL; L21223; AAA39973.1; JOINED; Genomic_DNA.
DR CCDS; CCDS24018.1; -. [P29121-1]
DR PIR; A54306; A54306.
DR RefSeq; NP_032819.1; NM_008793.2. [P29121-1]
DR AlphaFoldDB; P29121; -.
DR SMR; P29121; -.
DR BioGRID; 202060; 1.
DR STRING; 10090.ENSMUSP00000020340; -.
DR MEROPS; S08.074; -.
DR GlyGen; P29121; 1 site.
DR iPTMnet; P29121; -.
DR PhosphoSitePlus; P29121; -.
DR PaxDb; P29121; -.
DR PRIDE; P29121; -.
DR ProteomicsDB; 287970; -. [P29121-1]
DR ProteomicsDB; 287971; -. [P29121-2]
DR ProteomicsDB; 287972; -. [P29121-3]
DR ProteomicsDB; 287973; -. [P29121-4]
DR ProteomicsDB; 287974; -. [P29121-5]
DR ProteomicsDB; 287975; -. [P29121-6]
DR ProteomicsDB; 287976; -. [P29121-7]
DR ProteomicsDB; 287977; -. [P29121-8]
DR Antibodypedia; 1614; 156 antibodies from 24 providers.
DR DNASU; 18551; -.
DR Ensembl; ENSMUST00000020340; ENSMUSP00000020340; ENSMUSG00000020131. [P29121-1]
DR GeneID; 18551; -.
DR KEGG; mmu:18551; -.
DR UCSC; uc007gcs.2; mouse. [P29121-1]
DR CTD; 54760; -.
DR MGI; MGI:97514; Pcsk4.
DR VEuPathDB; HostDB:ENSMUSG00000020131; -.
DR eggNOG; KOG3525; Eukaryota.
DR GeneTree; ENSGT00940000161989; -.
DR HOGENOM; CLU_002976_4_0_1; -.
DR InParanoid; P29121; -.
DR OMA; ENPQGLW; -.
DR OrthoDB; 473018at2759; -.
DR PhylomeDB; P29121; -.
DR TreeFam; TF314277; -.
DR BRENDA; 3.4.21.B24; 3474.
DR BRENDA; 3.4.21.B25; 3474.
DR BioGRID-ORCS; 18551; 3 hits in 72 CRISPR screens.
DR PRO; PR:P29121; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P29121; protein.
DR Bgee; ENSMUSG00000020131; Expressed in spermatid and 158 other tissues.
DR ExpressionAtlas; P29121; baseline and differential.
DR Genevisible; P29121; MM.
DR GO; GO:0002080; C:acrosomal membrane; IDA:MGI.
DR GO; GO:0001669; C:acrosomal vesicle; IDA:UniProtKB.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
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; IMP:MGI.
DR GO; GO:0007339; P:binding of sperm to zona pellucida; IMP:MGI.
DR GO; GO:0009566; P:fertilization; IDA:UniProtKB.
DR GO; GO:0016486; P:peptide hormone processing; IBA:GO_Central.
DR GO; GO:0016485; P:protein processing; ISS:UniProtKB.
DR GO; GO:0022414; P:reproductive process; IMP:UniProtKB.
DR GO; GO:0048240; P:sperm capacitation; IDA:UniProtKB.
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; IPR008979; Galactose-bd-like_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 SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF52743; SSF52743; 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 2: Evidence at transcript level;
KW Alternative splicing; Cleavage on pair of basic residues;
KW Cytoplasmic vesicle; Glycoprotein; Hydrolase; Membrane; Protease;
KW Reference proteome; Serine protease; Signal; Zymogen.
FT SIGNAL 1..26
FT /evidence="ECO:0000250"
FT PROPEP 27..110
FT /evidence="ECO:0000255"
FT /id="PRO_0000027098"
FT CHAIN 111..655
FT /note="Proprotein convertase subtilisin/kexin type 4"
FT /id="PRO_0000027099"
FT DOMAIN 123..437
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT DOMAIN 446..580
FT /note="P/Homo B"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01173"
FT ACT_SITE 155
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 196
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 370
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT CARBOHYD 472
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 22..60
FT /note="Missing (in isoform 5)"
FT /evidence="ECO:0000303|PubMed:8020970"
FT /id="VSP_011266"
FT VAR_SEQ 51..60
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000303|PubMed:8020970"
FT /id="VSP_011267"
FT VAR_SEQ 273..282
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:8020970"
FT /id="VSP_011268"
FT VAR_SEQ 590..655
FT /note="VTSRARACVQRDTEGLCQESHSPLSILAGLCLISSQQWWWLYSHPQQPVTEG
FT QASCHPPVTPAAAA -> KVTVPSPSWQDSASSPASSGGGSTATHSSQ (in
FT isoform 3)"
FT /evidence="ECO:0000303|PubMed:1448111"
FT /id="VSP_011271"
FT VAR_SEQ 590..655
FT /note="VTSRARACVQRDTEGLCQESHSPLSILAGLCLISSQQWWWLYSHPQQPVTEG
FT QASCHPPVTPAAAA -> DSASSPASSGGGSTATHSSQ (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:1448111"
FT /id="VSP_011272"
FT VAR_SEQ 590..617
FT /note="Missing (in isoform 8)"
FT /evidence="ECO:0000303|PubMed:8020970"
FT /id="VSP_011270"
FT VAR_SEQ 590..608
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000303|PubMed:8020970"
FT /id="VSP_011269"
FT CONFLICT 65
FT /note="D -> N (in Ref. 3; AAA39973)"
FT /evidence="ECO:0000305"
FT CONFLICT 87
FT /note="R -> P (in Ref. 3; AAA39973)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 655 AA; 73214 MW; 4E4E32CEDECBCB59 CRC64;
MRPSQTELWL GLTLTLALLA VRWASAQAPI YVSSWAVRVT KGYQEAERLA RKFGFVNLGQ
IFPDDQYFHL RHRGVAQQSL TPHWGHRLRL KKDPKVRWFE QQTLRRRVKR SLVVPTDPWF
SKQWYMNKEI QQDLNILKAW NQGLTGRGVV ISILDDGIEK DHPDLWANYD PLASYDFNDY
DPDPQPRYTP NDENRHGTRC AGEVSATANN GFCGAGVAFN ARIGGVRMLD GAITDIVEAQ
SLSLQPQHIH IYSASWGPED DGRTVDGPGL LTQEAFRRGV TKGRQGLGTL FIWASGNGGL
HYDNCNCDGY TNSIHTLSVG STTRQGRVPW YSEACASTFT TTFSSGVVTD PQIVTTDLHH
QCTDKHTGTS ASAPLAAGMI ALALEANPLL TWRDLQHLVV RASRPAQLQA EDWRINGVGR
QVSHHYGYGL LDAGLLVDLA RVWLPTKPQK KCAIRVVHTP TPILPRMLVP KNVTACSDGS
RRRLIRSLEH VQVQLSLSYS RRGDLEIFLT SPMGTRSTLV AIRPLDISGQ GYNNWIFMST
HYWDEDPQGL WTLGLENKGY YFNTGTLYYY TLLLYGTAED MTARPQAPQV TSRARACVQR
DTEGLCQESH SPLSILAGLC LISSQQWWWL YSHPQQPVTE GQASCHPPVT PAAAA
