Reactome | UniProt:Q8NBP7 PCSK9

Schema > ReferenceGeneProduct > Entries

UniProt:Q8NBP7 PCSK9 Show undefined attributes

chain	signal peptide:1-30 propeptide:31-152 chain:153-692
checksum	9BCB9418B90AEE23
comment	FUNCTION 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 (PubMed:18039658). 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 (PubMed:17461796, PubMed:18197702, PubMed:18799458, PubMed:22074827). 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 (PubMed:18660751). 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.COFACTOR Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.SUBUNIT 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 (PubMed:18799458).INTERACTION 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 colocalizes 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.ALTERNATIVE PRODUCTS Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.DOMAIN The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities.DOMAIN The catalytic domain is responsible for mediating its self-association.PTM Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation.PTM 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.PTM Phosphorylation protects the propeptide against proteolysis.POLYMORPHISM Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia.POLYMORPHISM Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776].DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the peptidase S8 family.
crossReference	[DatabaseIdentifier:12148712] PDB:6OLZ [DatabaseIdentifier:12814991] ZINC target:Q8NBP7 [DatabaseIdentifier:12811659] ZINC - Substances:PCSK9_HUMAN [DatabaseIdentifier:12809448] ZINC - Predictions - Purchasable:PCSK9_HUMAN [DatabaseIdentifier:12364263] RefSeq:NP_777596.2 [DatabaseIdentifier:12284659] Pharos - Targets:Q8NBP7 [DatabaseIdentifier:12263343] PRO:Q8NBP7 [DatabaseIdentifier:12172265] PDB:6U2N [DatabaseIdentifier:12161644] PDB:3M0C [DatabaseIdentifier:12172248] PDB:6MV5 [DatabaseIdentifier:12161660] PDB:3GCW [DatabaseIdentifier:12172241] PDB:5VLP [DatabaseIdentifier:12172240] PDB:6U36 [DatabaseIdentifier:12172239] PDB:5VLK [DatabaseIdentifier:12172246] PDB:6E4Z [DatabaseIdentifier:12161648] PDB:2W2P [DatabaseIdentifier:12172254] PDB:7S5H [DatabaseIdentifier:12172243] PDB:2PMW [DatabaseIdentifier:12172252] PDB:2QTW [DatabaseIdentifier:12172236] PDB:8FPQ [DatabaseIdentifier:12172277] PDB:5VL7 [DatabaseIdentifier:12172233] PDB:5OCA [DatabaseIdentifier:12172244] PDB:8VDV [DatabaseIdentifier:12172242] PDB:6U38 [DatabaseIdentifier:12172278] PDB:2P4E [DatabaseIdentifier:12172271] PDB:6XIC [DatabaseIdentifier:12172247] PDB:6E4Y [DatabaseIdentifier:12172255] PDB:6U3X [DatabaseIdentifier:12172260] PDB:8FVN [DatabaseIdentifier:12172276] PDB:5VLA [DatabaseIdentifier:12161645] PDB:2W2M [DatabaseIdentifier:12161646] PDB:2W2N [DatabaseIdentifier:12172250] PDB:7ANQ [DatabaseIdentifier:12172272] PDB:6XIF [DatabaseIdentifier:12172268] PDB:5VLH [DatabaseIdentifier:12172245] PDB:3H42 [DatabaseIdentifier:12172275] PDB:6U2F [DatabaseIdentifier:12172235] PDB:6U3I [DatabaseIdentifier:12172279] PDB:6U26 [DatabaseIdentifier:12161658] PDB:3BPS [DatabaseIdentifier:12172263] PDB:8FVL [DatabaseIdentifier:12161666] PDB:4NE9 [DatabaseIdentifier:12172253] PDB:7KFA [DatabaseIdentifier:12172274] PDB:4K8R [DatabaseIdentifier:12172261] PDB:4NMX [DatabaseIdentifier:12172234] PDB:3SQO [DatabaseIdentifier:12172266] PDB:6XIB [DatabaseIdentifier:12172262] PDB:8FVO [DatabaseIdentifier:12172238] PDB:5VLL [DatabaseIdentifier:12172258] PDB:8FVP [DatabaseIdentifier:12172269] PDB:6U2P [DatabaseIdentifier:11470677] ENSEMBL:ENSG00000169174 [DatabaseIdentifier:11567628] ENSEMBL:ENSP00000303208 [DatabaseIdentifier:11690327] ENSEMBL:ENST00000302118 [DatabaseIdentifier:11779910] Guide to Pharmacology - Targets:2388 [DatabaseIdentifier:11786740] GeneCards:PCSK9 [DatabaseIdentifier:11802207] GlyGen:Q8NBP7 [DatabaseIdentifier:11830333] HMDB Protein:HMDBP07935 [DatabaseIdentifier:11839819] HPA:ENSG00000169174-PCSK9 [DatabaseIdentifier:12124347] OpenTargets:ENSG00000169174 [DatabaseIdentifier:12135628] Orphanet:PCSK9 [DatabaseIdentifier:12172249] PDB:8WFR [DatabaseIdentifier:12172257] PDB:2XTJ [DatabaseIdentifier:12172273] PDB:6XIE [DatabaseIdentifier:12161665] PDB:3P5C [DatabaseIdentifier:12148662] PDB:6OM0 [DatabaseIdentifier:12148709] PDB:6OM7 [DatabaseIdentifier:12172259] PDB:8FVQ [DatabaseIdentifier:12172270] PDB:6XID [DatabaseIdentifier:12172264] PDB:8FVM [DatabaseIdentifier:12161647] PDB:2W2O [DatabaseIdentifier:12172237] PDB:8FPO [DatabaseIdentifier:12172251] PDB:7S5G [DatabaseIdentifier:12161662] PDB:3GCX [DatabaseIdentifier:12161650] PDB:2W2Q [DatabaseIdentifier:12172267] PDB:4OV6 [DatabaseIdentifier:12161663] PDB:3P5B [DatabaseIdentifier:12172256] PDB:7KEV
databaseName	UniProt
dbId	97863
description	recommendedName: Proprotein convertase subtilisin/kexin type 9 ecNumber: 3.4.21.- alternativeName: Neural apoptosis-regulated convertase 1 shortName: NARC-1 alternativeName: Proprotein convertase 9 shortName: PC9 alternativeName: Subtilisin/kexin-like protease PC9
displayName	UniProt:Q8NBP7 PCSK9
geneName	PCSK9 NARC1 PSEC0052
identifier	Q8NBP7
isSequenceChanged	false
keyword	3D-structure Alternative splicing Apoptosis Autocatalytic cleavage Calcium Cholesterol metabolism Cytoplasm Direct protein sequencing Disease variant Disulfide bond Endoplasmic reticulum Endosome Glycoprotein Golgi apparatus Hydrolase Lipid metabolism Lysosome Phosphoprotein Protease Proteomics identification Reference proteome Secreted Serine protease Signal Steroid metabolism Sterol metabolism Sulfation Zymogen
modified	[InstanceEdit:9926675] Weiser, Joel, 2024-11-03
moleculeType	Protein
name	PCSK9
physicalEntity	[EntityWithAccessionedSequence:R-HSA-8956745] PCSK9 [endoplasmic reticulum lumen] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-8956943] p-PCSK9 [endoplasmic reticulum lumen] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-6784727] PCSK9 [extracellular region] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-8855128] PCSK9 [lysosomal membrane] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-6784823] PCSK9 [endolysosome membrane] - Homo sapiens
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:ensembl:ENSG00000169174] ENSEMBL:ENSG00000169174 PCSK9 [ReferenceDNASequence:12737410] UCSC:Q8NBP7 PCSK9 [ReferenceDNASequence:11335656] BioGPS Gene:255738 PCSK9 [ReferenceDNASequence:11399214] COSMIC - genes:PCSK9 PCSK9 [ReferenceDNASequence:11412026] CTD Gene:255738 PCSK9 [ReferenceDNASequence:11436176] dbSNP Gene:255738 PCSK9 [ReferenceDNASequence:11818379] HGNC:20001 PCSK9 [ReferenceDNASequence:11876837] KEGG:hsa:255738 PCSK9 [ReferenceDNASequence:11965445] Monarch:255738 PCSK9 [ReferenceDNASequence:12049538] NCBI Gene:255738 PCSK9 [ReferenceDNASequence:12109759] OMIM:607786 PCSK9
referenceTranscript	[ReferenceRNASequence:12546089] RefSeq:NM_174936.3 PCSK9
schemaClass	ReferenceGeneProduct
secondaryIdentifier	PCSK9_HUMAN A8T640 C0JYY9 Q5PSM5 Q5SZQ2
sequenceLength	692
species	[Species:48887] Homo sapiens
stId	uniprot:Q8NBP7
url	http://purl.uniprot.org/uniprot/Q8NBP7

Referrals

(referenceEntity)	[EntityWithAccessionedSequence:R-HSA-8956745] PCSK9 [endoplasmic reticulum lumen] [EntityWithAccessionedSequence:R-HSA-8956943] p-PCSK9 [endoplasmic reticulum lumen] [EntityWithAccessionedSequence:R-HSA-6784727] PCSK9 [extracellular region] [EntityWithAccessionedSequence:R-HSA-8855128] PCSK9 [lysosomal membrane] [EntityWithAccessionedSequence:R-HSA-6784823] PCSK9 [endolysosome membrane]
(referenceSequence)	[ModifiedResidue:8956896] phosphorylated residue at unknown position
(interactor)	[UndirectedInteraction:11246245] UniProt:P08253 <-> UniProt:Q8NBP7 (IntAct) [UndirectedInteraction:11249337] UniProt:Q8NBP7 <-> UniProt:P01130 (IntAct) [UndirectedInteraction:11249339] UniProt:Q8NBP7 <-> UniProt:P07355 (IntAct) [UndirectedInteraction:11249343] UniProt:Q8NBP7 <-> IntAct:EBI-8785901 (IntAct)