PCSK9_RAT
ID PCSK9_RAT Reviewed; 691 AA.
AC P59996; Q5I6U6;
DT 07-NOV-2003, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2003, sequence version 1.
DT 03-AUG-2022, entry version 140.
DE RecName: Full=Proprotein convertase subtilisin/kexin type 9;
DE EC=3.4.21.-;
DE AltName: Full=Neural apoptosis-regulated convertase 1;
DE Short=NARC-1;
DE AltName: Full=Proprotein convertase 9;
DE Short=PC9;
DE AltName: Full=Subtilisin/kexin-like protease PC9;
DE Flags: Precursor;
GN Name=Pcsk9; Synonyms=Narc1;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE.
RA Chiang L.W.;
RT "Narc-1, novel subtilase-like homologs.";
RL Patent number WO0157081, 09-AUG-2001.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RA Petkov P., Grozdanov P., Hadjiolova K., Karagyozov L., Dabeva M.;
RT "Rat proprotein convertase subtilisin/kexin type 9.";
RL Submitted (DEC-2004) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP CHARACTERIZATION.
RX PubMed=12552133; DOI=10.1073/pnas.0335507100;
RA Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B.,
RA Stifani S., Basak A., Prat A., Chretien M.;
RT "The secretory proprotein convertase neural apoptosis-regulated convertase
RT 1 (NARC-1): liver regeneration and neuronal differentiation.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003).
RN [5]
RP CHARACTERIZATION, AUTOCATALYTIC CLEAVAGE SITE, AND MUTAGENESIS OF GLN-151;
RP SER-152; HIS-225 AND SER-385.
RX PubMed=14622975; DOI=10.1016/j.abb.2003.09.011;
RA Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y.,
RA Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S., Kennedy J.D.,
RA DiStefano P.S., Wood A., Bingham B.;
RT "Functional characterization of Narc 1, a novel proteinase related to
RT proteinase K.";
RL Arch. Biochem. Biophys. 420:55-67(2003).
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 -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 8-11.;
CC Temperature dependence:
CC Optimum temperature is 37 degrees Celsius.;
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 -!- TISSUE SPECIFICITY: Highly expressed in 12-day embryo. In the adult,
CC strongly expressed in liver, small intestine, jejunum, and to a lesser
CC extent in kidney, lung, spleen and thymus. Expression in the liver is
CC up-regulated following partial hepatectomy.
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAC60363.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AX207690; CAC60363.1; ALT_INIT; Unassigned_DNA.
DR EMBL; AY847775; AAW31850.1; -; mRNA.
DR EMBL; BC133063; AAI33064.1; -; mRNA.
DR RefSeq; NP_954862.2; NM_199253.2.
DR AlphaFoldDB; P59996; -.
DR SMR; P59996; -.
DR STRING; 10116.ENSRNOP00000008536; -.
DR MEROPS; S08.039; -.
DR GlyGen; P59996; 1 site.
DR iPTMnet; P59996; -.
DR PhosphoSitePlus; P59996; -.
DR PaxDb; P59996; -.
DR ABCD; P59996; 2 sequenced antibodies.
DR Ensembl; ENSRNOT00000008535; ENSRNOP00000008536; ENSRNOG00000006280.
DR GeneID; 298296; -.
DR KEGG; rno:298296; -.
DR UCSC; RGD:728909; rat.
DR CTD; 255738; -.
DR RGD; 728909; Pcsk9.
DR eggNOG; KOG1153; Eukaryota.
DR GeneTree; ENSGT00490000043472; -.
DR HOGENOM; CLU_011263_11_0_1; -.
DR InParanoid; P59996; -.
DR OMA; CNKAAWR; -.
DR OrthoDB; 921536at2759; -.
DR PhylomeDB; P59996; -.
DR TreeFam; TF106271; -.
DR Reactome; R-RNO-381426; Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs).
DR Reactome; R-RNO-8866427; VLDLR internalisation and degradation.
DR Reactome; R-RNO-8957275; Post-translational protein phosphorylation.
DR Reactome; R-RNO-8964038; LDL clearance.
DR PRO; PR:P59996; -.
DR Proteomes; UP000002494; Chromosome 5.
DR Bgee; ENSRNOG00000006280; Expressed in liver and 6 other tissues.
DR Genevisible; P59996; RN.
DR GO; GO:0009986; C:cell surface; ISS:UniProtKB.
DR GO; GO:0030134; C:COPII-coated ER to Golgi transport vesicle; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; IDA:RGD.
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; ISO:RGD.
DR GO; GO:1990666; C:PCSK9-LDLR complex; ISO:RGD.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:RGD.
DR GO; GO:0034185; F:apolipoprotein binding; ISS:UniProtKB.
DR GO; GO:0034190; F:apolipoprotein receptor binding; ISO:RGD.
DR GO; GO:0030169; F:low-density lipoprotein particle binding; ISS:UniProtKB.
DR GO; GO:0050750; F:low-density lipoprotein particle receptor binding; ISS:HGNC-UCL.
DR GO; GO:0043621; F:protein self-association; ISS:UniProtKB.
DR GO; GO:0004252; F:serine-type endopeptidase activity; ISS:HGNC-UCL.
DR GO; GO:0030547; F:signaling receptor inhibitor activity; ISO:RGD.
DR GO; GO:0019871; F:sodium channel inhibitor activity; ISO:RGD.
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; ISO:RGD.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IDA:HGNC-UCL.
DR GO; GO:0009267; P:cellular response to starvation; IDA:HGNC-UCL.
DR GO; GO:0042632; P:cholesterol homeostasis; IEP:RGD.
DR GO; GO:0008203; P:cholesterol metabolic process; ISO:RGD.
DR GO; GO:0001822; P:kidney development; IEP:HGNC-UCL.
DR GO; GO:0042157; P:lipoprotein metabolic process; ISO:RGD.
DR GO; GO:0001889; P:liver development; IEP:HGNC-UCL.
DR GO; GO:0032802; P:low-density lipoprotein particle receptor catabolic process; ISS:UniProtKB.
DR GO; GO:0032799; P:low-density lipoprotein receptor particle metabolic process; ISO:RGD.
DR GO; GO:0007041; P:lysosomal transport; ISO:RGD.
DR GO; GO:0010989; P:negative regulation of low-density lipoprotein particle clearance; ISO:RGD.
DR GO; GO:1905596; P:negative regulation of low-density lipoprotein particle receptor binding; ISO:RGD.
DR GO; GO:1905598; P:negative regulation of low-density lipoprotein receptor activity; ISO:RGD.
DR GO; GO:0002091; P:negative regulation of receptor internalization; ISO:RGD.
DR GO; GO:0001920; P:negative regulation of receptor recycling; ISO:RGD.
DR GO; GO:1905601; P:negative regulation of receptor-mediated endocytosis involved in cholesterol transport; ISO:RGD.
DR GO; GO:2000650; P:negative regulation of sodium ion transmembrane transporter activity; ISO:RGD.
DR GO; GO:0022008; P:neurogenesis; IEP:HGNC-UCL.
DR GO; GO:0030182; P:neuron differentiation; ISS:HGNC-UCL.
DR GO; GO:0006644; P:phospholipid metabolic process; ISO:RGD.
DR GO; GO:0032805; P:positive regulation of low-density lipoprotein particle receptor catabolic process; ISO:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IDA:HGNC-UCL.
DR GO; GO:0002092; P:positive regulation of receptor internalization; ISO:RGD.
DR GO; GO:0016540; P:protein autoprocessing; IDA:RGD.
DR GO; GO:0016485; P:protein processing; IDA:RGD.
DR GO; GO:0032803; P:regulation of low-density lipoprotein particle receptor catabolic process; ISO:RGD.
DR GO; GO:0043523; P:regulation of neuron apoptotic process; ISS:UniProtKB.
DR GO; GO:0010469; P:regulation of signaling receptor activity; ISO:RGD.
DR GO; GO:0006641; P:triglyceride metabolic process; ISO:RGD.
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; IPR037045; S8pro/Inhibitor_I9_sf.
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 1: Evidence at protein 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:0000255"
FT PROPEP 31..151
FT /id="PRO_0000027124"
FT CHAIN 152..691
FT /note="Proprotein convertase subtilisin/kexin type 9"
FT /id="PRO_0000027125"
FT DOMAIN 154..441
FT /note="Peptidase S8"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01240"
FT REGION 449..691
FT /note="C-terminal domain"
FT /evidence="ECO:0000250"
FT MOTIF 495..497
FT /note="Cell attachment site"
FT /evidence="ECO:0000255"
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 SITE 217..218
FT /note="Cleavage; by furin and PCSK5"
FT /evidence="ECO:0000250"
FT MOD_RES 37
FT /note="Sulfotyrosine"
FT /evidence="ECO:0000250"
FT MOD_RES 46
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT MOD_RES 687
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NBP7"
FT CARBOHYD 532
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000250"
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"
FT MUTAGEN 151
FT /note="Q->E,N: No effect; when associated with A-152."
FT /evidence="ECO:0000269|PubMed:14622975"
FT MUTAGEN 151
FT /note="Q->I: Abolishes autocleavage; when associated with
FT V-152."
FT /evidence="ECO:0000269|PubMed:14622975"
FT MUTAGEN 152
FT /note="S->A: No effect; when associated with E-151 or N-
FT 151."
FT /evidence="ECO:0000269|PubMed:14622975"
FT MUTAGEN 152
FT /note="S->V: Abolishes autocleavage; when associated with
FT I-151."
FT /evidence="ECO:0000269|PubMed:14622975"
FT MUTAGEN 225
FT /note="H->W: Abolishes autocleavage."
FT /evidence="ECO:0000269|PubMed:14622975"
FT MUTAGEN 385
FT /note="S->A: Abolishes autocleavage."
FT /evidence="ECO:0000269|PubMed:14622975"
SQ SEQUENCE 691 AA; 74709 MW; 8084A880CCAE5BA6 CRC64;
MGIRCSTWLR WPLSPQLLLL LLLCPTGSRA QDEDGDYEEL MLALPSQEDS LVDEASHVAT
ATFRRCSKEA WRLPGTYVVV LMEETQRLQV EQTAHRLQTW AARRGYVIKV LHVFYDLFPG
FLVKMSSDLL GLALKLPHVE YIEEDSLVFA QSIPWNLERI IPAWQQTEED SSPDGSSQVE
VYLLDTSIQS GHREIEGRVT ITDFNSVPEE DGTRFHRQAS KCDSHGTHLA GVVSGRDAGV
AKGTSLHSLR VLNCQGKGTV SGTLIGLEFI RKSQLIQPSG PLVVLLPLAG GYSRILNTAC
QRLARTGVVL VAAAGNFRDD ACLYSPASAP EVITVGATNA QDQPVTLGTL GTNFGRCVDL
FAPGKDIIGA SSDCSTCYMS QSGTSQAAAH VAGIVAMMLN RDPALTLAEL RQRLILFSTK
DVINMAWFPE DQRVLTPNRV ATLPPSTQET GGQLLCRTVW SAHSGPTRTA TATARCAPEE
ELLSCSSFSR SGRRRGDRIE AIGGQQVCKA LNAFGGEGVY AVARCCLLPR VNCSIHNTPA
ARAGPQTPVH CHQKDHVLTG CSFHWEVENL RAQQQPLLRS RHQPGQCVGH QEASVHASCC
HAPGLECKIK EHGIAGPAEQ VTVACEAGWT LTGCNVLPGA SLPLGAYSVD NVCVARIRDA
GRADRTSEEA TVAAAICCRS RPSAKASWVH Q
