PCSK9_ATEGE
ID PCSK9_ATEGE Reviewed; 690 AA.
AC A8T6A1;
DT 05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 15-JAN-2008, sequence version 1.
DT 03-AUG-2022, entry version 57.
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 Ateles geoffroyi (Black-handed spider monkey) (Geoffroy's spider monkey).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini; Atelidae;
OC Atelinae; Ateles.
OX NCBI_TaxID=9509;
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: 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; EF692508; ABV59228.1; -; mRNA.
DR AlphaFoldDB; A8T6A1; -.
DR SMR; A8T6A1; -.
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; Secreted; Serine protease; Signal; Steroid metabolism;
KW Sterol metabolism; Sulfation; Zymogen.
FT SIGNAL 1..28
FT /evidence="ECO:0000250"
FT PROPEP 29..150
FT /evidence="ECO:0000250"
FT /id="PRO_0000318272"
FT CHAIN 151..690
FT /note="Proprotein convertase subtilisin/kexin type 9"
FT /id="PRO_0000318273"
FT DOMAIN 75..147
FT /note="Inhibitor I9"
FT /evidence="ECO:0000255"
FT DOMAIN 153..459
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT REGION 448..690
FT /note="C-terminal domain"
FT /evidence="ECO:0000250"
FT ACT_SITE 184
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 224
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 384
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT SITE 150..151
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250"
FT SITE 216..217
FT /note="Cleavage; by furin and PCSK5"
FT /evidence="ECO:0000250"
FT MOD_RES 36
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250"
FT MOD_RES 45
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT MOD_RES 686
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT CARBOHYD 531
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 221..253
FT /evidence="ECO:0000255"
FT DISULFID 321..356
FT /evidence="ECO:0000255"
FT DISULFID 455..525
FT /evidence="ECO:0000255"
FT DISULFID 475..524
FT /evidence="ECO:0000255"
FT DISULFID 484..507
FT /evidence="ECO:0000255"
FT DISULFID 532..599
FT /evidence="ECO:0000255"
FT DISULFID 550..598
FT /evidence="ECO:0000255"
FT DISULFID 560..586
FT /evidence="ECO:0000255"
FT DISULFID 606..677
FT /evidence="ECO:0000255"
FT DISULFID 624..676
FT /evidence="ECO:0000255"
FT DISULFID 633..652
FT /evidence="ECO:0000255"
SQ SEQUENCE 690 AA; 74296 MW; 0B1F64C531766323 CRC64;
MGTVRSRRLW WPLPLLLLLL RGPAGARAQE DDDGDYEELV LALRSEEDGL AEAPQHGATA
TFHRCAKDPW RLPGTYVVVL KEETQRSQPE RTARRLQAQA ARRGYLIKLL HVFHDLLPGF
LVKMSRDLLE LALRLPHVDY IEEDSYVFAQ SIPWNLERIT PARYRADEYQ PPNGGSLVEV
YLLDTSIQSG HREIEGRVMV TDFESVPEED GTRFHRQASK CDSHGTHLAG VVSGRDAGVA
KGASLRSLRV LNCQGKGTVS STLIGLEFIR KNQLVQPVGP LVVLLPLAGG YSRVLNAACQ
RLAKAGVVLV AAAGNFRDDA CLYSPASAPE VITVGATNAQ DQPVTLGTLG TNFGRCVDLF
APGEDIIGAS SDCSTCFVSR SGTSQAAAHV AGIAAMMLSA EPELTLAELR QRLIHFSAKD
VINEAWFPED QRVLTPNLVA ALPPSTHGAG WQLFCRTVWS AHSGPTRMAT AMARCAPDEE
LLSCSSFSRS GKRRGERIKA QGGRRVCLAH NAFGGEGVYA IARCCLLPQA NCSVHTAPPA
GAGMGTRVHC HHQGHVLTGC SSHWEVEDLG THKPSVLRPR VQPDQCMGHS GASTHASCCH
APGLECKVKE HGLPAPQEQV TVACEEGWTL TGCSALPGTS HVLGAYAVDD TCVVRSRDVS
TTGNTSEQAV AAVAICCRSR HLAQASQELQ
