UniProtKB - Q80W65 (PCSK9_MOUSE)
Proprotein convertase subtilisin/kexin type 9
Pcsk9
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 PublicationsCofactori
Activity regulationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Active sitei | 189 | Charge relay systemPROSITE-ProRule annotation | 1 | |
Active sitei | 229 | Charge relay systemPROSITE-ProRule annotation | 1 | |
Active sitei | 389 | Charge relay systemPROSITE-ProRule annotation | 1 |
GO - Molecular functioni
- apolipoprotein binding Source: UniProtKB
- apolipoprotein receptor binding Source: MGI
- low-density lipoprotein particle binding Source: UniProtKB
- low-density lipoprotein particle receptor binding Source: HGNC-UCL
- protein self-association Source: UniProtKB
- serine-type endopeptidase activity Source: HGNC-UCL
- signaling receptor inhibitor activity Source: MGI
- sodium channel inhibitor activity Source: MGI
- very-low-density lipoprotein particle binding Source: UniProtKB
- very-low-density lipoprotein particle receptor binding Source: MGI
GO - Biological processi
- apoptotic process Source: UniProtKB-KW
- cellular response to insulin stimulus Source: HGNC-UCL
- cellular response to starvation Source: HGNC-UCL
- cholesterol homeostasis Source: HGNC-UCL
- cholesterol metabolic process Source: MGI
- kidney development Source: HGNC-UCL
- lipoprotein metabolic process Source: MGI
- liver development Source: HGNC-UCL
- low-density lipoprotein particle receptor catabolic process Source: UniProtKB
- low-density lipoprotein receptor particle metabolic process Source: MGI
- lysosomal transport Source: MGI
- negative regulation of low-density lipoprotein particle clearance Source: MGI
- negative regulation of low-density lipoprotein particle receptor binding Source: MGI
- negative regulation of low-density lipoprotein receptor activity Source: MGI
- negative regulation of receptor internalization Source: MGI
- negative regulation of receptor-mediated endocytosis involved in cholesterol transport Source: MGI
- negative regulation of receptor recycling Source: MGI
- negative regulation of sodium ion transmembrane transporter activity Source: MGI
- neurogenesis Source: HGNC-UCL
- neuron differentiation Source: HGNC-UCL
- phospholipid metabolic process Source: MGI
- positive regulation of low-density lipoprotein particle receptor catabolic process Source: MGI
- positive regulation of neuron apoptotic process Source: HGNC-UCL
- positive regulation of receptor internalization Source: MGI
- protein autoprocessing Source: HGNC-UCL
- protein processing Source: MGI
- regulation of low-density lipoprotein particle receptor catabolic process Source: MGI
- regulation of neuron apoptotic process Source: UniProtKB
- regulation of signaling receptor activity Source: MGI
- triglyceride metabolic process Source: MGI
Keywordsi
Molecular function | Hydrolase, Protease, Serine protease |
Biological process | Apoptosis, Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism |
Ligand | Calcium |
Enzyme and pathway databases
BRENDAi | 3.4.21.61, 3474 |
Reactomei | R-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
MEROPSi | S08.039 |
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 |
Organismi | Mus musculus (Mouse) |
Taxonomic identifieri | 10090 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus |
Proteomesi |
|
Organism-specific databases
MGIi | MGI:2140260, Pcsk9 |
VEuPathDBi | HostDB:ENSMUSG00000044254 |
Subcellular locationi
Endosome
- Endosome By similarity
Golgi apparatus
- Golgi apparatus By similarity
Cytoplasm and Cytosol
- Cytoplasm By similarity
Endoplasmic reticulum
- Endoplasmic reticulum By similarity
Lysosome
- Lysosome By similarity
Extracellular region or secreted
Other locations
- Cell surface By similarity
Note: Autocatalytic cleavage is required to transport it from the endoplasmic reticulum to the Golgi apparatus and for the secretion of the mature protein. Localizes to the endoplasmic reticulum in the absence of LDLR and co-localizes to the cell surface and to the endosomes/lysosomes in the presence of LDLR. The sorting to the cell surface and endosomes is required in order to fully promote LDLR degradation (By similarity).By similarity
Endoplasmic reticulum
- endoplasmic reticulum Source: MGI
- endoplasmic reticulum lumen Source: Reactome
- rough endoplasmic reticulum Source: MGI
Endosome
- early endosome Source: UniProtKB
- late endosome Source: UniProtKB
Extracellular region or secreted
- extracellular region Source: MGI
- extracellular space Source: HGNC-UCL
Golgi apparatus
- Golgi apparatus Source: UniProtKB
Lysosome
- lysosome Source: UniProtKB
Plasma Membrane
- plasma membrane Source: MGI
Other locations
- cell surface Source: UniProtKB
- COPII-coated ER to Golgi transport vesicle Source: MGI
- cytoplasm Source: UniProtKB
- PCSK9-AnxA2 complex Source: BHF-UCL
- PCSK9-LDLR complex Source: BHF-UCL
- perinuclear region of cytoplasm Source: MGI
Keywords - Cellular componenti
Cytoplasm, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, SecretedPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Signal peptidei | 1 – 34 | Sequence analysisAdd BLAST | 34 | |
PropeptideiPRO_0000027122 | 35 – 155 | Add BLAST | 121 | |
ChainiPRO_0000027123 | 156 – 694 | Proprotein convertase subtilisin/kexin type 9Add BLAST | 539 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 41 | SulfotyrosineBy similarity | 1 | |
Modified residuei | 50 | Phosphoserine1 Publication | 1 | |
Disulfide bondi | 226 ↔ 258 | Sequence analysis | ||
Disulfide bondi | 326 ↔ 361 | Sequence analysis | ||
Disulfide bondi | 460 ↔ 530 | Sequence analysis | ||
Disulfide bondi | 480 ↔ 529 | Sequence analysis | ||
Disulfide bondi | 489 ↔ 512 | Sequence analysis | ||
Glycosylationi | 536 | N-linked (GlcNAc...) asparagineBy similarity | 1 | |
Disulfide bondi | 537 ↔ 604 | Sequence analysis | ||
Disulfide bondi | 555 ↔ 603 | Sequence analysis | ||
Disulfide bondi | 565 ↔ 591 | Sequence analysis | ||
Disulfide bondi | 611 ↔ 682 | Sequence analysis | ||
Disulfide bondi | 629 ↔ 681 | Sequence analysis | ||
Disulfide bondi | 638 ↔ 657 | Sequence analysis | ||
Modified residuei | 691 | PhosphoserineBy similarity | 1 |
Post-translational modificationi
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sitei | 155 – 156 | Cleavage; by autolysisBy similarity | 2 | |
Sitei | 221 – 222 | Cleavage; by furin and PCSK5By similarity | 2 |
Keywords - PTMi
Autocatalytic cleavage, Disulfide bond, Glycoprotein, Phosphoprotein, Sulfation, ZymogenProteomic databases
CPTACi | non-CPTAC-3369 |
MaxQBi | Q80W65 |
PaxDbi | Q80W65 |
PeptideAtlasi | Q80W65 |
PRIDEi | Q80W65 |
ProteomicsDBi | 288003 |
PTM databases
GlyGeni | Q80W65, 1 site |
iPTMneti | Q80W65 |
PhosphoSitePlusi | Q80W65 |
Expressioni
Tissue specificityi
Developmental stagei
Inductioni
Gene expression databases
Bgeei | ENSMUSG00000044254, Expressed in lobe of liver and 199 other tissues |
Genevisiblei | Q80W65, 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 similarityGO - Molecular functioni
- apolipoprotein binding Source: UniProtKB
- apolipoprotein receptor binding Source: MGI
- low-density lipoprotein particle receptor binding Source: HGNC-UCL
- protein self-association Source: UniProtKB
- very-low-density lipoprotein particle binding Source: UniProtKB
- very-low-density lipoprotein particle receptor binding Source: MGI
Protein-protein interaction databases
ComplexPortali | CPX-129, LDLR-PCSK9 complex CPX-141, ANXA2-PCSK9 complex |
IntActi | Q80W65, 1 interactor |
MINTi | Q80W65 |
STRINGi | 10090.ENSMUSP00000055757 |
Miscellaneous databases
RNActi | Q80W65, protein |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 158 – 470 | Peptidase S8PROSITE-ProRule annotationAdd BLAST | 313 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 453 – 694 | C-terminal domainBy similarityAdd BLAST | 242 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 499 – 501 | Cell attachment siteSequence analysis | 3 |
Domaini
Sequence similaritiesi
Keywords - Domaini
SignalPhylogenomic databases
eggNOGi | KOG1153, Eukaryota |
GeneTreei | ENSGT00490000043472 |
HOGENOMi | CLU_011263_11_0_1 |
InParanoidi | Q80W65 |
OMAi | CNKAAWR |
OrthoDBi | 921536at2759 |
PhylomeDBi | Q80W65 |
TreeFami | TF106271 |
Family and domain databases
CDDi | cd04077, Peptidases_S8_PCSK9_ProteinaseK_like, 1 hit |
Gene3Di | 3.30.70.80, 1 hit 3.40.50.200, 1 hit |
InterProi | View protein in InterPro IPR041254, PCSK9_C IPR041052, PCSK9_C2 IPR041051, PCSK9_C3 IPR034193, PCSK9_ProteinaseK-like IPR000209, Peptidase_S8/S53_dom IPR036852, Peptidase_S8/S53_dom_sf IPR015500, Peptidase_S8_subtilisin-rel IPR010259, S8pro/Inhibitor_I9 IPR037045, S8pro/Inhibitor_I9_sf |
Pfami | View protein in Pfam PF05922, Inhibitor_I9, 1 hit PF18459, PCSK9_C1, 1 hit PF18464, PCSK9_C2, 1 hit PF18463, PCSK9_C3, 1 hit PF00082, Peptidase_S8, 1 hit |
PRINTSi | PR00723, SUBTILISIN |
SUPFAMi | SSF52743, SSF52743, 1 hit |
PROSITEi | View protein in PROSITE PS51892, SUBTILASE, 1 hit |
i Sequence
Sequence statusi: Complete.
: The displayed sequence is further processed into a mature form. Sequence processingi
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
Sequence cautioni
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 17 – 19 | Missing in CAC60362 (Ref. 1) Curated | 3 | |
Sequence conflicti | 34 | A → T in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 189 | D → G in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 196 | H → Y in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 200 | E → A in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 305 | R → Q in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 534 | R → H in CAC60362 (Ref. 1) Curated | 1 | |
Sequence conflicti | 626 | T → A in CAC60362 (Ref. 1) Curated | 1 |
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 |
CCDSi | CCDS18418.1 |
RefSeqi | NP_705793.1, NM_153565.2 |
Genome annotation databases
Ensembli | ENSMUST00000049507; ENSMUSP00000055757; ENSMUSG00000044254 |
GeneIDi | 100102 |
KEGGi | mmu:100102 |
UCSCi | uc008tyi.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 |
CCDSi | CCDS18418.1 |
RefSeqi | NP_705793.1, NM_153565.2 |
3D structure databases
AlphaFoldDBi | Q80W65 |
SMRi | Q80W65 |
ModBasei | Search... |
Protein-protein interaction databases
ComplexPortali | CPX-129, LDLR-PCSK9 complex CPX-141, ANXA2-PCSK9 complex |
IntActi | Q80W65, 1 interactor |
MINTi | Q80W65 |
STRINGi | 10090.ENSMUSP00000055757 |
Protein family/group databases
MEROPSi | S08.039 |
PTM databases
GlyGeni | Q80W65, 1 site |
iPTMneti | Q80W65 |
PhosphoSitePlusi | Q80W65 |
Proteomic databases
CPTACi | non-CPTAC-3369 |
MaxQBi | Q80W65 |
PaxDbi | Q80W65 |
PeptideAtlasi | Q80W65 |
PRIDEi | Q80W65 |
ProteomicsDBi | 288003 |
Protocols and materials databases
ABCDi | Q80W65, 1 sequenced antibody |
Antibodypediai | 33231, 1026 antibodies from 43 providers |
DNASUi | 100102 |
Genome annotation databases
Ensembli | ENSMUST00000049507; ENSMUSP00000055757; ENSMUSG00000044254 |
GeneIDi | 100102 |
KEGGi | mmu:100102 |
UCSCi | uc008tyi.2, mouse |
Organism-specific databases
CTDi | 255738 |
MGIi | MGI:2140260, Pcsk9 |
VEuPathDBi | HostDB:ENSMUSG00000044254 |
Phylogenomic databases
eggNOGi | KOG1153, Eukaryota |
GeneTreei | ENSGT00490000043472 |
HOGENOMi | CLU_011263_11_0_1 |
InParanoidi | Q80W65 |
OMAi | CNKAAWR |
OrthoDBi | 921536at2759 |
PhylomeDBi | Q80W65 |
TreeFami | TF106271 |
Enzyme and pathway databases
BRENDAi | 3.4.21.61, 3474 |
Reactomei | R-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
BioGRID-ORCSi | 100102, 2 hits in 77 CRISPR screens |
PROi | PR:Q80W65 |
RNActi | Q80W65, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSMUSG00000044254, Expressed in lobe of liver and 199 other tissues |
Genevisiblei | Q80W65, MM |
Family and domain databases
CDDi | cd04077, Peptidases_S8_PCSK9_ProteinaseK_like, 1 hit |
Gene3Di | 3.30.70.80, 1 hit 3.40.50.200, 1 hit |
InterProi | View protein in InterPro IPR041254, PCSK9_C IPR041052, PCSK9_C2 IPR041051, PCSK9_C3 IPR034193, PCSK9_ProteinaseK-like IPR000209, Peptidase_S8/S53_dom IPR036852, Peptidase_S8/S53_dom_sf IPR015500, Peptidase_S8_subtilisin-rel IPR010259, S8pro/Inhibitor_I9 IPR037045, S8pro/Inhibitor_I9_sf |
Pfami | View protein in Pfam PF05922, Inhibitor_I9, 1 hit PF18459, PCSK9_C1, 1 hit PF18464, PCSK9_C2, 1 hit PF18463, PCSK9_C3, 1 hit PF00082, Peptidase_S8, 1 hit |
PRINTSi | PR00723, SUBTILISIN |
SUPFAMi | SSF52743, SSF52743, 1 hit |
PROSITEi | View protein in PROSITE PS51892, SUBTILASE, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | PCSK9_MOUSE | |
Accessioni | Q80W65Primary (citable) accession number: Q80W65 Secondary accession number(s): B1AZI4 Q8CFT6 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 7, 2003 |
Last sequence update: | November 7, 2003 | |
Last modified: | May 25, 2022 | |
This is version 164 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- Peptidase families
Classification of peptidase families and list of entries - MGD cross-references
Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot - SIMILARITY comments
Index of protein domains and families