PCSK9_PLEMO
ID PCSK9_PLEMO Reviewed; 684 AA.
AC A8T677;
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 Plecturocebus moloch (Dusky titi monkey) (Callicebus moloch).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Platyrrhini;
OC Pitheciidae; Callicebinae; Plecturocebus.
OX NCBI_TaxID=9523;
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; EF692504; ABV59224.1; -; mRNA.
DR AlphaFoldDB; A8T677; -.
DR SMR; A8T677; -.
DR PRIDE; A8T677; -.
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..151
FT /evidence="ECO:0000250"
FT /id="PRO_0000318276"
FT CHAIN 152..684
FT /note="Proprotein convertase subtilisin/kexin type 9"
FT /id="PRO_0000318277"
FT DOMAIN 75..148
FT /note="Inhibitor I9"
FT /evidence="ECO:0000255"
FT DOMAIN 154..460
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT REGION 451..684
FT /note="C-terminal domain"
FT /evidence="ECO:0000250"
FT ACT_SITE 185
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 225
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT ACT_SITE 385
FT /note="Charge relay system"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT SITE 151..152
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000250"
FT SITE 217..218
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 CARBOHYD 532
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 222..254
FT /evidence="ECO:0000255"
FT DISULFID 322..357
FT /evidence="ECO:0000255"
FT DISULFID 456..526
FT /evidence="ECO:0000255"
FT DISULFID 476..525
FT /evidence="ECO:0000255"
FT DISULFID 485..508
FT /evidence="ECO:0000255"
FT DISULFID 533..600
FT /evidence="ECO:0000255"
FT DISULFID 551..599
FT /evidence="ECO:0000255"
FT DISULFID 561..587
FT /evidence="ECO:0000255"
FT DISULFID 607..678
FT /evidence="ECO:0000255"
FT DISULFID 625..677
FT /evidence="ECO:0000255"
FT DISULFID 634..653
FT /evidence="ECO:0000255"
SQ SEQUENCE 684 AA; 73231 MW; 672C74FFCFAB33DE CRC64;
MGTVSSRRLW WPLPLLLLLL LGPPGARAQE DDDGDYEELV LALRSEEDGP ADALQHGATA
TFHRCAKDPW RLPGTYVVVL KDSDAHRSQP ERTARRLQAQ AARRGYLIKL LHVFHHLLPG
FLVKMSRDLL ELALRLPHVD YIEEDSSVFA QSIPWNLERI TPARYRADEY QPPNGGSLVE
VYLLDTSIQS SHREIEGRVM VTDFESVPEE DGTRFHRQAS KCDSHGTHLA GVVSGRDAGV
AKGASLRSLH VLNCQGKGTV SSALIGLEFI RKSQLVQPVG PLVVLLPLAG GYSRVLNAAC
RRLAGAGVVL VAAAGNFRDD ACLYSPASAP EVITVGATNA QDQPLTLGTL GTNFGRCVDL
FAPGEDIIGA SSDCSTCFVS RSGTSQAAAH VAGIAAMMLS AEPELTLAEL RQRLIHFSAK
DVINEAWFPE DQRVLTPNLV ATLPPSTHGA GWQLFCRTVW SAHSGPTRMA TAMARCAPDE
ELLSCSSFSR SGKRRGERIE AQGGRRVCLA PNAFGGEGVY AVARCCLLPQ ANCSVHTAPP
AGAGMGTRAH CHQQGHVLTG CSSHWEMKDL GTHKPPVLKP RGQPDQCMGH SGASTHASCC
YAPGLECKVK EHGLPAPQEQ VTVACEEGWT LTGCSALPGT SHVLGAYAVD DTCVVRSRDV
STTGSTSEEA VAAVAICCRS RHLA
