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Protein

Proprotein convertase subtilisin/kexin type 9

Gene

Pcsk9

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation. Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway. Inhibits epithelial Na+ channel (ENaC)-mediated Na+ absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways (By similarity).By similarity

Cofactori

Ca2+By similarity

Enzyme regulationi

Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA (By similarity).By similarity

pH dependencei

Optimum pH is 8-11.

Temperature dependencei

Optimum temperature is 37 degrees Celsius.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei185Charge relay systemBy similarity1
Active sitei225Charge relay systemBy similarity1
Active sitei385Charge relay systemBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionHydrolase, Protease, Serine protease
Biological processApoptosis, Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism
LigandCalcium

Enzyme and pathway databases

ReactomeiR-RNO-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-RNO-8866427 VLDLR internalisation and degradation
R-RNO-8957275 Post-translational protein phosphorylation
R-RNO-8964038 LDL clearance

Protein family/group databases

MEROPSiS08.039

Names & Taxonomyi

Protein namesi
Recommended name:
Proprotein convertase subtilisin/kexin type 9 (EC:3.4.21.-)
Alternative name(s):
Neural apoptosis-regulated convertase 1
Short name:
NARC-1
Proprotein convertase 9
Short name:
PC9
Subtilisin/kexin-like protease PC9
Gene namesi
Name:Pcsk9
Synonyms:Narc1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 5

Organism-specific databases

RGDi728909 Pcsk9

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi151Q → E or N: No effect; when associated with A-152. 1 Publication1
Mutagenesisi151Q → I: Abolishes autocleavage; when associated with V-152. 1 Publication1
Mutagenesisi152S → A: No effect; when associated with E-151 or N-151. 1 Publication1
Mutagenesisi152S → V: Abolishes autocleavage; when associated with I-151. 1 Publication1
Mutagenesisi225H → W: Abolishes autocleavage. 1 Publication1
Mutagenesisi385S → A: Abolishes autocleavage. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 30Sequence analysisAdd BLAST30
PropeptideiPRO_000002712431 – 151Add BLAST121
ChainiPRO_0000027125152 – 691Proprotein convertase subtilisin/kexin type 9Add BLAST540

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei37SulfotyrosineBy similarity1
Modified residuei46PhosphoserineBy similarity1
Disulfide bondi222 ↔ 254Sequence analysis
Disulfide bondi322 ↔ 357Sequence analysis
Disulfide bondi456 ↔ 526Sequence analysis
Disulfide bondi476 ↔ 525Sequence analysis
Disulfide bondi485 ↔ 508Sequence analysis
Glycosylationi532N-linked (GlcNAc...) asparagineBy similarity1
Disulfide bondi533 ↔ 600Sequence analysis
Disulfide bondi551 ↔ 599Sequence analysis
Disulfide bondi561 ↔ 587Sequence analysis
Disulfide bondi607 ↔ 678Sequence analysis
Disulfide bondi625 ↔ 677Sequence analysis
Disulfide bondi634 ↔ 653Sequence analysis
Modified residuei687PhosphoserineBy similarity1

Post-translational modificationi

Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation.By similarity
Undergoes autocatalytic cleavage in the endoplasmic reticulum to release the propeptide from the N-terminus and the cleavage of the propeptide is strictly required for its maturation and activation. The cleaved propeptide however remains associated with the catalytic domain through non-covalent interactions, preventing potential substrates from accessing its active site. As a result, it is secreted from cells as a propeptide-containing, enzymatically inactive protein (By similarity).By similarity
Phosphorylation protects the propeptide against proteolysis.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei151 – 152Cleavage; by autolysis2
Sitei217 – 218Cleavage; by furin and PCSK5By similarity2

Keywords - PTMi

Autocatalytic cleavage, Disulfide bond, Glycoprotein, Phosphoprotein, Sulfation, Zymogen

Proteomic databases

PaxDbiP59996
PRIDEiP59996

PTM databases

iPTMnetiP59996
PhosphoSitePlusiP59996

Expressioni

Tissue specificityi

Highly expressed in 12-day embryo. In the adult, strongly expressed in liver, small intestine, jejunum, and to a lesser extent in kidney, lung, spleen and thymus. Expression in the liver is up-regulated following partial hepatectomy.

Gene expression databases

BgeeiENSRNOG00000006280
GenevisibleiP59996 RN

Interactioni

Subunit structurei

Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full-length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR.By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008536

Structurei

3D structure databases

ProteinModelPortaliP59996
SMRiP59996
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini181 – 422Peptidase S8Add BLAST242

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni449 – 691C-terminal domainBy similarityAdd BLAST243

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi495 – 497Cell attachment siteSequence analysis3

Domaini

The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities.By similarity
The catalytic domain is responsible for mediating its self-association.By similarity

Sequence similaritiesi

Belongs to the peptidase S8 family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG1153 Eukaryota
COG1404 LUCA
GeneTreeiENSGT00490000043472
HOGENOMiHOG000049267
HOVERGENiHBG053530
InParanoidiP59996
KOiK13050
OMAiHVLTGCS
OrthoDBiEOG091G067E
PhylomeDBiP59996
TreeFamiTF106271

Family and domain databases

CDDicd04077 Peptidases_S8_PCSK9_Proteinase, 1 hit
Gene3Di3.30.70.80, 1 hit
3.40.50.200, 1 hit
InterProiView protein in InterPro
IPR034193 PCSK9_ProteinaseK-like
IPR000209 Peptidase_S8/S53_dom
IPR036852 Peptidase_S8/S53_dom_sf
IPR015500 Peptidase_S8_subtilisin-rel
IPR037045 S8pro/Inhibitor_I9_sf
PfamiView protein in Pfam
PF00082 Peptidase_S8, 1 hit
PRINTSiPR00723 SUBTILISIN
SUPFAMiSSF52743 SSF52743, 1 hit

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P59996-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGIRCSTWLR WPLSPQLLLL LLLCPTGSRA QDEDGDYEEL MLALPSQEDS
60 70 80 90 100
LVDEASHVAT ATFRRCSKEA WRLPGTYVVV LMEETQRLQV EQTAHRLQTW
110 120 130 140 150
AARRGYVIKV LHVFYDLFPG FLVKMSSDLL GLALKLPHVE YIEEDSLVFA
160 170 180 190 200
QSIPWNLERI IPAWQQTEED SSPDGSSQVE VYLLDTSIQS GHREIEGRVT
210 220 230 240 250
ITDFNSVPEE DGTRFHRQAS KCDSHGTHLA GVVSGRDAGV AKGTSLHSLR
260 270 280 290 300
VLNCQGKGTV SGTLIGLEFI RKSQLIQPSG PLVVLLPLAG GYSRILNTAC
310 320 330 340 350
QRLARTGVVL VAAAGNFRDD ACLYSPASAP EVITVGATNA QDQPVTLGTL
360 370 380 390 400
GTNFGRCVDL FAPGKDIIGA SSDCSTCYMS QSGTSQAAAH VAGIVAMMLN
410 420 430 440 450
RDPALTLAEL RQRLILFSTK DVINMAWFPE DQRVLTPNRV ATLPPSTQET
460 470 480 490 500
GGQLLCRTVW SAHSGPTRTA TATARCAPEE ELLSCSSFSR SGRRRGDRIE
510 520 530 540 550
AIGGQQVCKA LNAFGGEGVY AVARCCLLPR VNCSIHNTPA ARAGPQTPVH
560 570 580 590 600
CHQKDHVLTG CSFHWEVENL RAQQQPLLRS RHQPGQCVGH QEASVHASCC
610 620 630 640 650
HAPGLECKIK EHGIAGPAEQ VTVACEAGWT LTGCNVLPGA SLPLGAYSVD
660 670 680 690
NVCVARIRDA GRADRTSEEA TVAAAICCRS RPSAKASWVH Q
Length:691
Mass (Da):74,709
Last modified:November 7, 2003 - v1
Checksum:i8084A880CCAE5BA6
GO

Sequence cautioni

The sequence CAC60363 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX207690 Unassigned DNA Translation: CAC60363.1 Different initiation.
AY847775 mRNA Translation: AAW31850.1
BC133063 mRNA Translation: AAI33064.1
RefSeqiNP_954862.2, NM_199253.2
UniGeneiRn.19195

Genome annotation databases

EnsembliENSRNOT00000008535; ENSRNOP00000008536; ENSRNOG00000006280
GeneIDi298296
KEGGirno:298296
UCSCiRGD:728909 rat

Similar proteinsi

Entry informationi

Entry nameiPCSK9_RAT
AccessioniPrimary (citable) accession number: P59996
Secondary accession number(s): Q5I6U6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 7, 2003
Last sequence update: November 7, 2003
Last modified: May 23, 2018
This is version 121 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Peptidase families
    Classification of peptidase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

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