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PCSK9_PANPA
ID   PCSK9_PANPA             Reviewed;         692 AA.
AC   A8T655;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   02-SEP-2008, sequence version 2.
DT   03-AUG-2022, entry version 55.
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   Pan paniscus (Pygmy chimpanzee) (Bonobo).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Pan.
OX   NCBI_TaxID=9597;
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).
RN   [2]
RP   SEQUENCE REVISION TO 15-16; 104; 278; 499; 602; 649-650; 658; 664; 666; 672
RP   AND 685.
RA   Ding K., McDonough S.J., Kullo I.J.;
RL   Submitted (JAN-2008) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Crucial player in the regulation of plasma cholesterol
CC       homeostasis. Binds to low-density lipid receptor family members: low
CC       density lipoprotein receptor (LDLR), very low density lipoprotein
CC       receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and
CC       apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation
CC       in intracellular acidic compartments. Acts via a non-proteolytic
CC       mechanism to enhance the degradation of the hepatic LDLR through a
CC       clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of
CC       LDLR from endosomes to the cell surface or direct it to lysosomes for
CC       degradation. Can induce ubiquitination of LDLR leading to its
CC       subsequent degradation. Inhibits intracellular degradation of APOB via
CC       the autophagosome/lysosome pathway in a LDLR-independent manner.
CC       Involved in the disposal of non-acetylated intermediates of BACE1 in
CC       the early secretory pathway. Inhibits epithelial Na(+) channel (ENaC)-
CC       mediated Na(+) absorption by reducing ENaC surface expression primarily
CC       by increasing its proteasomal degradation. Regulates neuronal apoptosis
CC       via modulation of LRP8/APOER2 levels and related anti-apoptotic
CC       signaling pathways (By similarity). {ECO:0000250}.
CC   -!- COFACTOR:
CC       Name=Ca(2+); Xref=ChEBI:CHEBI:29108; Evidence={ECO:0000250};
CC   -!- ACTIVITY REGULATION: Its proteolytic activity is autoinhibited by the
CC       non-covalent binding of the propeptide to the catalytic domain.
CC       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 SCNN1G. The
CC       pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts
CC       (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the
CC       interaction inhibits the degradation of LDLR.
CC       {ECO:0000250|UniProtKB:Q8NBP7}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Secreted {ECO:0000250}.
CC       Endosome {ECO:0000250}. Lysosome {ECO:0000250}. Cell surface
CC       {ECO:0000250}. Endoplasmic reticulum {ECO:0000250}. Golgi apparatus
CC       {ECO:0000250}. Note=Autocatalytic cleavage is required to transport it
CC       from the endoplasmic reticulum to the Golgi apparatus and for the
CC       secretion of the mature protein. Localizes to the endoplasmic reticulum
CC       in the absence of LDLR and colocalizes to the cell surface and to the
CC       endosomes/lysosomes in the presence of LDLR. The sorting to the cell
CC       surface and endosomes is required in order to fully promote LDLR
CC       degradation (By similarity). {ECO:0000250}.
CC   -!- DOMAIN: The C-terminal domain (CRD) is essential for the LDLR-binding
CC       and degrading activities. {ECO:0000250}.
CC   -!- DOMAIN: The catalytic domain is responsible for mediating its self-
CC       association. {ECO:0000250}.
CC   -!- PTM: Cleavage by furin and PCSK5 generates a truncated inactive protein
CC       that is unable to induce LDLR degradation. {ECO:0000250}.
CC   -!- PTM: Undergoes autocatalytic cleavage in the endoplasmic reticulum to
CC       release the propeptide from the N-terminus and the cleavage of the
CC       propeptide is strictly required for its maturation and activation. The
CC       cleaved propeptide however remains associated with the catalytic domain
CC       through non-covalent interactions, preventing potential substrates from
CC       accessing its active site. As a result, it is secreted from cells as a
CC       propeptide-containing, enzymatically inactive protein (By similarity).
CC       {ECO:0000250}.
CC   -!- PTM: Phosphorylation protects the propeptide against proteolysis.
CC       {ECO:0000250}.
CC   -!- SIMILARITY: Belongs to the peptidase S8 family. {ECO:0000305}.
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DR   EMBL; EF692499; ABV59219.2; -; mRNA.
DR   AlphaFoldDB; A8T655; -.
DR   SMR; A8T655; -.
DR   STRING; 9597.XP_008966100.1; -.
DR   PRIDE; A8T655; -.
DR   eggNOG; KOG1153; Eukaryota.
DR   Proteomes; UP000240080; Unplaced.
DR   GO; GO:0009986; C:cell surface; ISS:UniProtKB.
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:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
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:0034185; F:apolipoprotein binding; ISS:UniProtKB.
DR   GO; GO:0030169; F:low-density lipoprotein particle binding; ISS:UniProtKB.
DR   GO; GO:0043621; F:protein self-association; ISS:UniProtKB.
DR   GO; GO:0004252; F:serine-type endopeptidase activity; IEA:InterPro.
DR   GO; GO:0034189; F:very-low-density lipoprotein particle binding; ISS:UniProtKB.
DR   GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR   GO; GO:0008203; P:cholesterol metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0032802; P:low-density lipoprotein particle receptor catabolic process; ISS:UniProtKB.
DR   GO; GO:0006508; P:proteolysis; IEA:UniProtKB-KW.
DR   GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
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_C1.
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   Cytoplasm; Disulfide bond; Endoplasmic reticulum; Endosome; Glycoprotein;
KW   Golgi apparatus; Hydrolase; Lipid metabolism; Lysosome; Phosphoprotein;
KW   Protease; Reference proteome; Secreted; Serine protease; Signal;
KW   Steroid metabolism; Sterol metabolism; Sulfation; Zymogen.
FT   SIGNAL          1..30
FT                   /evidence="ECO:0000250"
FT   PROPEP          31..152
FT                   /evidence="ECO:0000250"
FT                   /id="PRO_0000318288"
FT   CHAIN           153..692
FT                   /note="Proprotein convertase subtilisin/kexin type 9"
FT                   /id="PRO_0000318289"
FT   DOMAIN          77..149
FT                   /note="Inhibitor I9"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          155..461
FT                   /note="Peptidase S8"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT   REGION          450..692
FT                   /note="C-terminal domain"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        186
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT   ACT_SITE        226
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT   ACT_SITE        386
FT                   /note="Charge relay system"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT   SITE            152..153
FT                   /note="Cleavage; by autolysis"
FT                   /evidence="ECO:0000250"
FT   SITE            218..219
FT                   /note="Cleavage; by furin and PCSK5"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         38
FT                   /note="Sulfotyrosine"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         47
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT   MOD_RES         688
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT   CARBOHYD        533
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        223..255
FT                   /evidence="ECO:0000255"
FT   DISULFID        323..358
FT                   /evidence="ECO:0000255"
FT   DISULFID        457..527
FT                   /evidence="ECO:0000255"
FT   DISULFID        477..526
FT                   /evidence="ECO:0000255"
FT   DISULFID        486..509
FT                   /evidence="ECO:0000255"
FT   DISULFID        534..601
FT                   /evidence="ECO:0000255"
FT   DISULFID        552..600
FT                   /evidence="ECO:0000255"
FT   DISULFID        562..588
FT                   /evidence="ECO:0000255"
FT   DISULFID        608..679
FT                   /evidence="ECO:0000255"
FT   DISULFID        626..678
FT                   /evidence="ECO:0000255"
FT   DISULFID        635..654
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   692 AA;  74323 MW;  156BF19B0446895F CRC64;
     MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT
     TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAAHRGYLTK ILHVFHGLLP
     GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV
     EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG
     VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVRPV GPLVVLLPLA GGYSRVLNAA
     CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD
     LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA
     KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAVARCAPD
     EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP
     PAEAGMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC
     CRAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRNRD
     VSTAGSTSEE AVAAVAICCR SRHLAQASQE LQ
 
 
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