PCSK9

Protein identityUniProt · HPA

UniProt accession

Q8NBP7

Gene

PCSK9

Ensembl

ENSG00000169174

Chromosome

1

Canonical length

692 aa

Protein class

Disease related genes, Enzymes, FDA approved drug targets, Human disease related genes, Plasma proteins, Predicted intracellular proteins, Predicted secreted proteins

Secretome location

Secreted to blood

OverviewNCBI Gene

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

Canonical amino-acid sequenceUniProt

692 residues, UniProt reviewed canonical sequence.

>Q8NBP7|PCSK9
     1  MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT
    61  TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP
   121  GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV
   181  EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG
   241  VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA
   301  CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD
   361  LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA
   421  KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAVARCAPD
   481  EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP
   541  PAEASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC
   601  CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD
   661  VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ

LocalizationUniProt · AlphaFold · HPA

Whether an antibody against PCSK9 can act on the native protein depends on physical access: surface and secreted proteins are reachable by circulating antibodies, intracellular proteins usually are not.

Antibody reachability

Cell surface

Secreted

No

Transmembrane segments

0

Mean surface accessibility (rSASA)

0.27

Highest tissue expression

48 nTPM

Expression across tissuesHPA

DiseaseUniProt · ClinVar · IEDB · PubMed

Four sources answering four different questions about PCSK9.

Disease | AllUniProt

Conditions PCSK9 is implicated in, by any mechanism.

• Hypercholesterolemia, familial, 3 (FHCL3) MIM:603776

Disease | GeneticClinVar

18 pathogenic / likely-pathogenic of 1,539 ClinVar records.

Conditions with pathogenic or likely-pathogenic variants.

• Hypercholesterolemia, familial, 1
• Hypercholesterolemia, autosomal dominant, 3
• Familial hypercholesterolemia
• Cardiovascular phenotype
• Homozygous familial hypercholesterolemia

ReferencesPubMed · IEDB

Publications for PCSK9 from three distinct lines of evidence, kept separate because they answer different questions: whether antibodies are directed at the protein, whether a B-cell epitope has been mapped on it, and whether a T-cell epitope has. Each is labelled with its source.

Sources: PubMed — antigen-level antibody evidence from a custom retrieval. Records matching a controlled set of autoantibody terms (the MeSH descriptors Autoantibodies and Autoantigens, with title and abstract term variants) were obtained through NCBI E-utilities, and their titles and abstracts parsed for constructions that direct an antibody at a named protein rather than for co-occurrence. Captured names were resolved against UniProt nomenclature and each antigen adjudicated individually against the source text. Bibliographic records from PubMed and MeSH, U.S. National Library of Medicine; citation metrics from NIH iCite (Hutchins et al., PLoS Biology 2016). Titles link to PubMed; abstracts are not reproduced here. The NLM does not endorse this analysis.

Genetic constraint and essentialitygnomAD · DepMap

Does the body need this protein intact? Low LOEUF or a strong DepMap dependency means loss or blockade of the protein is likely to be felt.

gnomAD LOEUF (loss-of-function intolerance)

1.34

gnomAD pLI

0

gnomAD missense Z

0.27

DepMap mean gene effect

-0.19

DepMap dependency class

selective

Cancer expressionTCGA

Across TCGA tumor cohorts, this protein is over-expressed in roughly 4% of surveyed tumor types (aggregate summary; per-cohort expression, alteration, and survival load in the interactive view).

OntologyGO

Biological processes

• apoptotic process
• cellular response to insulin stimulus
• cellular response to starvation
• cholesterol homeostasis
• cholesterol metabolic process
• kidney development
• lipoprotein metabolic process
• liver development
• lysosomal transport
• negative regulation of low-density lipoprotein particle clearance
• negative regulation of receptor internalization
• negative regulation of receptor recycling
• negative regulation of receptor-mediated endocytosis involved in cholesterol transport
• negative regulation of sodium ion import across plasma membrane
• neurogenesis
• neuron differentiation
• phospholipid metabolic process
• positive regulation of low-density lipoprotein particle receptor catabolic process
• positive regulation of neuron apoptotic process
• positive regulation of receptor internalization
• protein autoprocessing
• regulation of neuron apoptotic process
• triglyceride metabolic process
• low-density lipoprotein particle receptor catabolic process

Molecular functions

• apolipoprotein binding
• apolipoprotein receptor binding
• endopeptidase activity
• low-density lipoprotein particle binding
• low-density lipoprotein particle receptor binding
• RNA binding
• serine-type endopeptidase activity
• signaling receptor inhibitor activity
• sodium channel inhibitor activity
• transporter inhibitor activity
• very-low-density lipoprotein particle binding
• very-low-density lipoprotein particle receptor binding

Cellular components

• cell surface
• COPII-coated ER to Golgi transport vesicle
• cytoplasm
• early endosome
• endolysosome membrane
• endoplasmic reticulum
• endoplasmic reticulum lumen
• extracellular region
• extracellular space
• extrinsic component of external side of plasma membrane
• Golgi apparatus
• late endosome
• lysosomal membrane
• lysosome
• PCSK9-AnxA2 complex
• PCSK9-LDLR complex
• perinuclear region of cytoplasm
• plasma membrane

Protein domainsUniProt · Pfam · InterPro

• Peptidase S8/S53 domain
• Peptidase S8, subtilisin-related
• Peptidase S8/S53 domain superfamily
• Subtilisin-like serine protease
• Subtilase family
• Peptidase S8 propeptide/proteinase inhibitor I9
• Proteinase K-like catalytic domain
• Peptidase S8 propeptide/proteinase inhibitor I9 superfamily
• Proprotein convertase subtilisin/kexin type 9, C-terminal domain 3
• Proprotein convertase subtilisin/kexin type 9, C-terminal domain 2
• Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1
• Peptidase inhibitor I9
• Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain
• Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain
• Proprotein convertase subtilisin-like/kexin type 9 C-terminal domain

KeywordsUniProt

• Apoptosis
• Autocatalytic cleavage
• Calcium
• Cholesterol metabolism
• Cytoplasm
• Disulfide bond
• Endoplasmic reticulum
• Endosome
• Glycoprotein
• Golgi apparatus
• Hydrolase
• Lipid metabolism
• Lysosome
• Phosphoprotein
• Protease
• Secreted
• Serine protease
• Signal
• Steroid metabolism
• Sterol metabolism
• Sulfation
• Zymogen

InteractionsUniProt · HPA

Protein binding partners of PCSK9 in the human serome: UniProt-annotated complex subunits plus reported interactors. Each links to its own Seroatlas record.

• APOB
• BACE1
• LDLR
• SCNN1A
• SCNN1B
• SCNN1G
• VLDLR
• LRP8