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UniProtKB - Q80W65 (PCSK9_MOUSE)

Protein

Proprotein convertase subtilisin/kexin type 9

Gene

Pcsk9

Organism
Mus musculus (Mouse)
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.2 Publications

Cofactori

Ca2+Curated

Activity regulationi

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei189Charge relay systemBy similarity1
Active sitei229Charge relay systemBy similarity1
Active sitei389Charge relay systemBy similarity1

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

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

Enzyme and pathway databases

ReactomeiR-MMU-381426 Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-MMU-8866427 VLDLR internalisation and degradation
R-MMU-8957275 Post-translational protein phosphorylation
R-MMU-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
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome 4

Organism-specific databases

MGIiMGI:2140260 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

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 34Sequence analysisAdd BLAST34
PropeptideiPRO_000002712235 – 155Add BLAST121
ChainiPRO_0000027123156 – 694Proprotein convertase subtilisin/kexin type 9Add BLAST539

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei41SulfotyrosineBy similarity1
Modified residuei50Phosphoserine1 Publication1
Disulfide bondi226 ↔ 258Sequence analysis
Disulfide bondi326 ↔ 361Sequence analysis
Disulfide bondi460 ↔ 530Sequence analysis
Disulfide bondi480 ↔ 529Sequence analysis
Disulfide bondi489 ↔ 512Sequence analysis
Glycosylationi536N-linked (GlcNAc...) asparagineBy similarity1
Disulfide bondi537 ↔ 604Sequence analysis
Disulfide bondi555 ↔ 603Sequence analysis
Disulfide bondi565 ↔ 591Sequence analysis
Disulfide bondi611 ↔ 682Sequence analysis
Disulfide bondi629 ↔ 681Sequence analysis
Disulfide bondi638 ↔ 657Sequence analysis
Modified residuei691PhosphoserineBy 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
Sitei155 – 156Cleavage; by autolysisBy similarity2
Sitei221 – 222Cleavage; by furin and PCSK5By similarity2

Keywords - PTMi

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

Proteomic databases

MaxQBiQ80W65
PaxDbiQ80W65
PeptideAtlasiQ80W65
PRIDEiQ80W65

PTM databases

iPTMnetiQ80W65
PhosphoSitePlusiQ80W65

Expressioni

Tissue specificityi

Hepatocytes, kidney mesenchymal cells, intestinal ileum, colon epithelia and embryonic brain telencephalon neurons.

Developmental stagei

In the embryo, expressed in the liver at day E9, in the skin and transiently in the telencephalon at day E12, and in the kidney, small intestine and cerebellum at E15.

Inductioni

Down-regulated following a high-cholesterol diet.1 Publication

Gene expression databases

BgeeiENSMUSG00000044254 Expressed in 173 organ(s), highest expression level in lobe of liver
CleanExiMM_PCSK9
GenevisibleiQ80W65 MM

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

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

ComplexPortaliCPX-129 LDLR-PCSK9 complex
CPX-141 ANXA2-PCSK9 complex
IntActiQ80W65, 1 interactor
MINTiQ80W65
STRINGi10090.ENSMUSP00000055757

Structurei

3D structure databases

ProteinModelPortaliQ80W65
SMRiQ80W65
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini185 – 423Peptidase S8Add BLAST239

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni453 – 694C-terminal domainBy similarityAdd BLAST242

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi499 – 501Cell 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
InParanoidiQ80W65
KOiK13050
OMAiKCDSHGT
OrthoDBiEOG091G067E
PhylomeDBiQ80W65
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.

Q80W65-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MGTHCSAWLR WPLLPLLPPL LLLLLLLCPT GAGAQDEDGD YEELMLALPS 
        60         70         80         90        100
QEDGLADEAA HVATATFRRC SKEAWRLPGT YIVVLMEETQ RLQIEQTAHR 
       110        120        130        140        150
LQTRAARRGY VIKVLHIFYD LFPGFLVKMS SDLLGLALKL PHVEYIEEDS 
       160        170        180        190        200
FVFAQSIPWN LERIIPAWHQ TEEDRSPDGS SQVEVYLLDT SIQGAHREIE 
       210        220        230        240        250
GRVTITDFNS VPEEDGTRFH RQASKCDSHG THLAGVVSGR DAGVAKGTSL 
       260        270        280        290        300
HSLRVLNCQG KGTVSGTLIG LEFIRKSQLI QPSGPLVVLL PLAGGYSRIL 
       310        320        330        340        350
NAACRHLART GVVLVAAAGN FRDDACLYSP ASAPEVITVG ATNAQDQPVT 
       360        370        380        390        400
LGTLGTNFGR CVDLFAPGKD IIGASSDCST CFMSQSGTSQ AAAHVAGIVA 
       410        420        430        440        450
RMLSREPTLT LAELRQRLIH FSTKDVINMA WFPEDQQVLT PNLVATLPPS 
       460        470        480        490        500
THETGGQLLC RTVWSAHSGP TRTATATARC APEEELLSCS SFSRSGRRRG 
       510        520        530        540        550
DWIEAIGGQQ VCKALNAFGG EGVYAVARCC LVPRANCSIH NTPAARAGLE 
       560        570        580        590        600
THVHCHQKDH VLTGCSFHWE VEDLSVRRQP ALRSRRQPGQ CVGHQAASVY 
       610        620        630        640        650
ASCCHAPGLE CKIKEHGISG PSEQVTVACE AGWTLTGCNV LPGASLTLGA 
       660        670        680        690 
YSVDNLCVAR VHDTARADRT SGEATVAAAI CCRSRPSAKA SWVQ
Length:694
Mass (Da):74,823
Last modified:November 7, 2003 - v2
Checksum:i977BD4BD1FAF98C0
GO

Sequence cautioni

The sequence AAP31672 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence BAE28934 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence CAC60362 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti17 – 19Missing in CAC60362 (Ref. 1) Curated3
Sequence conflicti34A → T in CAC60362 (Ref. 1) Curated1
Sequence conflicti189D → G in CAC60362 (Ref. 1) Curated1
Sequence conflicti196H → Y in CAC60362 (Ref. 1) Curated1
Sequence conflicti200E → A in CAC60362 (Ref. 1) Curated1
Sequence conflicti305R → Q in CAC60362 (Ref. 1) Curated1
Sequence conflicti534R → H in CAC60362 (Ref. 1) Curated1
Sequence conflicti626T → A in CAC60362 (Ref. 1) Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX207688 Unassigned DNA Translation: CAC60362.1 Different initiation.
AY273821 mRNA Translation: AAP31672.1 Different initiation.
AK149520 mRNA Translation: BAE28934.1 Different initiation.
AL954352 Genomic DNA No translation available.
BC038085 mRNA Translation: AAH38085.1
CCDSiCCDS18418.1
RefSeqiNP_705793.1, NM_153565.2
UniGeneiMm.133268

Genome annotation databases

EnsembliENSMUST00000049507; ENSMUSP00000055757; ENSMUSG00000044254
GeneIDi100102
KEGGimmu:100102
UCSCiuc008tyi.2 mouse

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX207688 Unassigned DNA Translation: CAC60362.1 Different initiation.
AY273821 mRNA Translation: AAP31672.1 Different initiation.
AK149520 mRNA Translation: BAE28934.1 Different initiation.
AL954352 Genomic DNA No translation available.
BC038085 mRNA Translation: AAH38085.1
CCDSiCCDS18418.1
RefSeqiNP_705793.1, NM_153565.2
UniGeneiMm.133268

3D structure databases

ProteinModelPortaliQ80W65
SMRiQ80W65
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

ComplexPortaliCPX-129 LDLR-PCSK9 complex
CPX-141 ANXA2-PCSK9 complex
IntActiQ80W65, 1 interactor
MINTiQ80W65
STRINGi10090.ENSMUSP00000055757

Protein family/group databases

MEROPSiS08.039

PTM databases

iPTMnetiQ80W65
PhosphoSitePlusiQ80W65

Proteomic databases

MaxQBiQ80W65
PaxDbiQ80W65
PeptideAtlasiQ80W65
PRIDEiQ80W65

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000049507; ENSMUSP00000055757; ENSMUSG00000044254
GeneIDi100102
KEGGimmu:100102
UCSCiuc008tyi.2 mouse

Organism-specific databases

CTDi255738
MGIiMGI:2140260 Pcsk9

Phylogenomic databases

eggNOGiKOG1153 Eukaryota
COG1404 LUCA
GeneTreeiENSGT00490000043472
HOGENOMiHOG000049267
HOVERGENiHBG053530
InParanoidiQ80W65
KOiK13050
OMAiKCDSHGT
OrthoDBiEOG091G067E
PhylomeDBiQ80W65
TreeFamiTF106271

Enzyme and pathway databases

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

Miscellaneous databases

PROiPR:Q80W65
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000044254 Expressed in 173 organ(s), highest expression level in lobe of liver
CleanExiMM_PCSK9
GenevisibleiQ80W65 MM

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
ProtoNetiSearch...

Entry informationi

Entry nameiPCSK9_MOUSE
AccessioniPrimary (citable) accession number: Q80W65
Secondary accession number(s): B1AZI4
, Q3UEH7, Q8BXW9, Q8CFT6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 7, 2003
Last sequence update: November 7, 2003
Last modified: November 7, 2018
This is version 144 of the entry and version 2 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. SIMILARITY comments
    Index of protein domains and families
  2. Peptidase families
    Classification of peptidase families and list of entries
  3. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
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