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Database: UniProt
Entry: PCSK9_MACMU
LinkDB: PCSK9_MACMU
Original site: PCSK9_MACMU 
ID   PCSK9_MACMU             Reviewed;         692 AA.
AC   A8T666;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   15-JAN-2008, sequence version 1.
DT   31-JUL-2019, entry version 65.
DE   RecName: Full=Proprotein convertase subtilisin/kexin type 9;
DE            EC=3.4.21.-;
DE   AltName: Full=Proprotein convertase 9;
DE            Short=PC9;
DE   AltName: Full=Subtilisin/kexin-like protease PC9;
DE   Flags: Precursor;
GN   Name=PCSK9;
OS   Macaca mulatta (Rhesus macaque).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Cercopithecidae; Cercopithecinae; Macaca.
OX   NCBI_TaxID=9544;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=17971861; DOI=10.1371/journal.pone.0001098;
RA   Ding K., McDonough S.J., Kullo I.J.;
RT   "Evidence for positive selection in the C-terminal domain of the
RT   cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14
RT   primate species.";
RL   PLoS ONE 2:E1098-E1098(2007).
CC   -!- FUNCTION: Crucial player in the regulation of plasma cholesterol
CC       homeostasis. Binds to low-density lipid receptor family members:
CC       low density lipoprotein receptor (LDLR), very low density
CC       lipoprotein receptor (VLDLR), apolipoprotein E receptor
CC       (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and
CC       promotes their degradation in intracellular acidic compartments.
CC       Acts via a non-proteolytic mechanism to enhance the degradation of
CC       the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway.
CC       May prevent the recycling of LDLR from endosomes to the cell
CC       surface or direct it to lysosomes for degradation. Can induce
CC       ubiquitination of LDLR leading to its subsequent degradation.
CC       Inhibits intracellular degradation of APOB via the
CC       autophagosome/lysosome pathway in a LDLR-independent manner.
CC       Involved in the disposal of non-acetylated intermediates of BACE1
CC       in the early secretory pathway. Inhibits epithelial Na(+) channel
CC       (ENaC)-mediated Na(+) absorption by reducing ENaC surface
CC       expression primarily by increasing its proteasomal degradation.
CC       Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels
CC       and related anti-apoptotic signaling pathways (By similarity).
CC       {ECO:0000250}.
CC   -!- COFACTOR:
CC       Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Its proteolytic activity is autoinhibited by
CC       the non-covalent binding of the propeptide to the catalytic
CC       domain. Inhibited by EGTA (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Monomer. Can self-associate to form dimers and higher
CC       multimers which may have increased LDLR degrading activity. The
CC       precursor protein but not the mature protein may form multimers.
CC       Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length
CC       immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and
CC       SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with
CC       LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat
CC       Annexin 1); the interaction inhibits the degradation of LDLR.
CC       {ECO:0000250|UniProtKB:Q8NBP7}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Secreted
CC       {ECO:0000250}. Endosome {ECO:0000250}. Lysosome {ECO:0000250}.
CC       Cell surface {ECO:0000250}. Endoplasmic reticulum {ECO:0000250}.
CC       Golgi apparatus {ECO:0000250}. Note=Autocatalytic cleavage is
CC       required to transport it from the endoplasmic reticulum to the
CC       Golgi apparatus and for the secretion of the mature protein.
CC       Localizes to the endoplasmic reticulum in the absence of LDLR and
CC       colocalizes to the cell surface and to the endosomes/lysosomes in
CC       the presence of LDLR. The sorting to the cell surface and
CC       endosomes is required in order to fully promote LDLR degradation
CC       (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: The C-terminal domain (CRD) is essential for the LDLR-
CC       binding and degrading activities. {ECO:0000250}.
CC   -!- DOMAIN: The catalytic domain is responsible for mediating its
CC       self-association. {ECO:0000250}.
CC   -!- PTM: Cleavage by furin and PCSK5 generates a truncated inactive
CC       protein that is unable to induce LDLR degradation. {ECO:0000250}.
CC   -!- PTM: Undergoes autocatalytic cleavage in the endoplasmic reticulum
CC       to release the propeptide from the N-terminus and the cleavage of
CC       the propeptide is strictly required for its maturation and
CC       activation. The cleaved propeptide however remains associated with
CC       the catalytic domain through non-covalent interactions, preventing
CC       potential substrates from accessing its active site. As a result,
CC       it is secreted from cells as a propeptide-containing,
CC       enzymatically inactive protein (By similarity). {ECO:0000250}.
CC   -!- PTM: Phosphorylation protects the propeptide against proteolysis.
CC       {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}.
DR   EMBL; EF692502; ABV59222.1; -; mRNA.
DR   RefSeq; NP_001106130.1; NM_001112660.1.
DR   SMR; A8T666; -.
DR   MEROPS; S08.039; -.
DR   PRIDE; A8T666; -.
DR   ABCD; A8T666; -.
DR   Ensembl; ENSMMUT00000008056; ENSMMUP00000007574; ENSMMUG00000005736.
DR   GeneID; 717147; -.
DR   KEGG; mcc:717147; -.
DR   CTD; 255738; -.
DR   InParanoid; A8T666; -.
DR   KO; K13050; -.
DR   Proteomes; UP000006718; Chromosome 1.
DR   ExpressionAtlas; A8T666; baseline.
DR   GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR   GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; IEA:Ensembl.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005769; C:early endosome; ISS:UniProtKB.
DR   GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR   GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR   GO; GO:0005794; C:Golgi apparatus; ISS:UniProtKB.
DR   GO; GO:0005770; C:late endosome; ISS:UniProtKB.
DR   GO; GO:0005764; C:lysosome; ISS:UniProtKB.
DR   GO; GO:1990667; C:PCSK9-AnxA2 complex; IEA:Ensembl.
DR   GO; GO:1990666; C:PCSK9-LDLR complex; IEA:Ensembl.
DR   GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; IEA:Ensembl.
DR   GO; GO:0034185; F:apolipoprotein binding; ISS:UniProtKB.
DR   GO; GO:0034190; F:apolipoprotein receptor binding; IEA:Ensembl.
DR   GO; GO:0030169; F:low-density lipoprotein particle binding; ISS:UniProtKB.
DR   GO; GO:0050750; F:low-density lipoprotein particle receptor binding; IEA:Ensembl.
DR   GO; GO:0043621; F:protein self-association; ISS:UniProtKB.
DR   GO; GO:0030547; F:receptor inhibitor activity; IEA:Ensembl.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; IBA:GO_Central.
DR   GO; GO:0019871; F:sodium channel inhibitor activity; IEA:Ensembl.
DR   GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB.
DR   GO; GO:0070326; F:very-low-density lipoprotein particle receptor binding; IEA:Ensembl.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0032869; P:cellular response to insulin stimulus; IEA:Ensembl.
DR   GO; GO:0009267; P:cellular response to starvation; IEA:Ensembl.
DR   GO; GO:0042632; P:cholesterol homeostasis; IEA:Ensembl.
DR   GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0001822; P:kidney development; IEA:Ensembl.
DR   GO; GO:0042157; P:lipoprotein metabolic process; IEA:Ensembl.
DR   GO; GO:0001889; P:liver development; IEA:Ensembl.
DR   GO; GO:0032802; P:low-density lipoprotein particle receptor catabolic process; ISS:UniProtKB.
DR   GO; GO:0007041; P:lysosomal transport; IEA:Ensembl.
DR   GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; IEA:Ensembl.
DR   GO; GO:1905596; P:negative regulation of low-density lipoprotein particle receptor binding; IEA:Ensembl.
DR   GO; GO:1905598; P:negative regulation of low-density lipoprotein receptor activity; IEA:Ensembl.
DR   GO; GO:0001920; P:negative regulation of receptor recycling; IEA:Ensembl.
DR   GO; GO:1905601; P:negative regulation of receptor-mediated endocytosis involved in cholesterol transport; IEA:Ensembl.
DR   GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; IEA:Ensembl.
DR   GO; GO:0030182; P:neuron differentiation; IEA:Ensembl.
DR   GO; GO:0006644; P:phospholipid metabolic process; IEA:Ensembl.
DR   GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; IEA:Ensembl.
DR   GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR   GO; GO:0002092; P:positive regulation of receptor internalization; IEA:Ensembl.
DR   GO; GO:0016540; P:protein autoprocessing; IEA:Ensembl.
DR   GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR   GO; GO:0006641; P:triglyceride metabolic process; IEA:Ensembl.
DR   CDD; cd04077; Peptidases_S8_PCSK9_ProteinaseK_like; 1.
DR   Gene3D; 3.30.70.80; -; 1.
DR   Gene3D; 3.40.50.200; -; 1.
DR   InterPro; IPR041254; PCSK9_C.
DR   InterPro; IPR041052; PCSK9_C2.
DR   InterPro; IPR041051; PCSK9_C3.
DR   InterPro; IPR034193; PCSK9_ProteinaseK-like.
DR   InterPro; IPR000209; Peptidase_S8/S53_dom.
DR   InterPro; IPR036852; Peptidase_S8/S53_dom_sf.
DR   InterPro; IPR015500; Peptidase_S8_subtilisin-rel.
DR   InterPro; IPR010259; S8pro/Inhibitor_I9.
DR   InterPro; IPR037045; S8pro/Inhibitor_I9_sf.
DR   Pfam; PF05922; Inhibitor_I9; 1.
DR   Pfam; PF18459; PCSK9_C1; 1.
DR   Pfam; PF18464; PCSK9_C2; 1.
DR   Pfam; PF18463; PCSK9_C3; 1.
DR   Pfam; PF00082; Peptidase_S8; 1.
DR   PRINTS; PR00723; SUBTILISIN.
DR   SUPFAM; SSF52743; SSF52743; 1.
DR   PROSITE; PS51892; SUBTILASE; 1.
PE   2: Evidence at transcript level;
KW   Apoptosis; Autocatalytic cleavage; Calcium; Cholesterol metabolism;
KW   Complete proteome; Cytoplasm; Disulfide bond; Endoplasmic reticulum;
KW   Endosome; Glycoprotein; Golgi apparatus; Hydrolase; Lipid metabolism;
KW   Lysosome; Phosphoprotein; Protease; Reference proteome; Secreted;
KW   Serine protease; Signal; Steroid metabolism; Sterol metabolism;
KW   Sulfation; Zymogen.
FT   SIGNAL        1     30       {ECO:0000250}.
FT   PROPEP       31    152       {ECO:0000250}.
FT                                /FTId=PRO_0000318284.
FT   CHAIN       153    692       Proprotein convertase subtilisin/kexin
FT                                type 9.
FT                                /FTId=PRO_0000318285.
FT   DOMAIN       77    149       Inhibitor I9. {ECO:0000255}.
FT   DOMAIN      155    444       Peptidase S8. {ECO:0000255|PROSITE-
FT                                ProRule:PRU01240}.
FT   REGION      450    692       C-terminal domain. {ECO:0000250}.
FT   ACT_SITE    186    186       Charge relay system.
FT                                {ECO:0000255|PROSITE-ProRule:PRU01240}.
FT   ACT_SITE    226    226       Charge relay system.
FT                                {ECO:0000255|PROSITE-ProRule:PRU01240}.
FT   ACT_SITE    386    386       Charge relay system.
FT                                {ECO:0000255|PROSITE-ProRule:PRU01240}.
FT   SITE        152    153       Cleavage; by autolysis. {ECO:0000250}.
FT   SITE        218    219       Cleavage; by furin and PCSK5.
FT                                {ECO:0000250}.
FT   MOD_RES      38     38       Sulfotyrosine. {ECO:0000250}.
FT   MOD_RES      47     47       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:Q8NBP7}.
FT   MOD_RES     688    688       Phosphoserine.
FT                                {ECO:0000250|UniProtKB:Q8NBP7}.
FT   CARBOHYD    533    533       N-linked (GlcNAc...) asparagine.
FT                                {ECO:0000255}.
FT   DISULFID    223    255       {ECO:0000255}.
FT   DISULFID    323    358       {ECO:0000255}.
FT   DISULFID    457    527       {ECO:0000255}.
FT   DISULFID    477    526       {ECO:0000255}.
FT   DISULFID    486    509       {ECO:0000255}.
FT   DISULFID    534    601       {ECO:0000255}.
FT   DISULFID    552    600       {ECO:0000255}.
FT   DISULFID    562    588       {ECO:0000255}.
FT   DISULFID    608    679       {ECO:0000255}.
FT   DISULFID    626    678       {ECO:0000255}.
FT   DISULFID    635    654       {ECO:0000255}.
SQ   SEQUENCE   692 AA;  74528 MW;  4B5E8C50731F40B3 CRC64;
     MGTVSSRRSW WPLPLPLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLADAPEHGA
     TATFHRCAKD PWRLPGTYVV VLKEETHRSQ SERTARRLQA QAARRGYLTK ILHVFHHLLP
     GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPARYRADE YQPPKGGSLV
     EVYLLDTSIQ SDHREIEGRV MVTDFESVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG
     VAKGAGLRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVFNAA
     CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD
     LFAPGEDIIG ASSDCSTCFV SRSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA
     KDVINEAWFP EDQRVLTPNL VAALPPSTHR AGWQLFCRTV WSAHSGPTRM ATAVARCAQD
     EELLSCSSFS RSGKRRGERI EAQGGKRVCR AHNAFGGEGV YAIARCCLLP QVNCSVHTAP
     PAGASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC
     CHAPGLECKV KEHGIPAPQE QVIVACEDGW TLTGCSPLPG TSHVLGAYAV DNTCVVRSRD
     VSTTGSTSKE AVAAVAICCR SRHLVQASQE LQ
//
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