Details for: PCSK9

Gene ID: 255738

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: PCSK9

Ensembl ID: ENSG00000169174

Description: proprotein convertase subtilisin/kexin type 9

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • goblet cell CL0000160
    CSI 3.84
    rCSI 3.63%
    PRS 99.1
  • epithelial cell CL0000066
    CSI 3.45
    rCSI 5.3%
    PRS 96.33
  • stem cell CL0000034
    CSI 3.22
    rCSI 3.1%
    PRS 99.22
  • colon epithelial cell CL0011108
    CSI 2.95
    rCSI 3.09%
    PRS 99.17
  • glial cell CL0000125
    CSI 1.59
    rCSI 6.05%
    PRS 97.55

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
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    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Proprotein convertase subtilisin/kexin type 9 ([PCSK9](/details-gene/255738)) is a secreted serine protease that has emerged as a central regulator of cholesterol metabolism. Its primary function is to negatively regulate the abundance of the low-density lipoprotein receptor (LDLR) on the cell surface, thereby controlling the clearance of LDL cholesterol from the bloodstream. As a key player in '[Cholesterol homeostasis](/details-go/GO:0042632)', it binds to the LDLR and targets the receptor for lysosomal degradation. **Overall**, expression data indicates that [PCSK9](/details-gene/255738) is highly significant in metabolically active and secretory cell types, including [goblet cell](/details-cell/CL0000160) and various [epithelial cell](/details-cell/CL0000066) populations, consistent with its role as a secreted protein with systemic effects on lipid metabolism. ## Cellular Roles and Expression Landscape The expression profile of [PCSK9](/details-gene/255738) highlights its prominent role in epithelial and secretory tissues. **Overall**, it shows the highest significance in [goblet cell](/details-cell/CL0000160) (CSI: 3.84), [epithelial cell](/details-cell/CL0000066) (CSI: 3.45), [stem cell](/details-cell/CL0000034) (CSI: 3.22), and [colon epithelial cell](/details-cell/CL0011108) (CSI: 2.95). This pattern suggests that beyond its well-characterized production in the liver, the gastrointestinal tract is a major site of [PCSK9](/details-gene/255738) expression and may contribute significantly to both local and systemic cholesterol regulation. Its notable significance in [stem cell](/details-cell/CL0000034) may point to a role in cellular differentiation or maintenance, particularly in renewing tissues like the intestinal epithelium. Furthermore, its expression in [glial cell](/details-cell/CL0000125) is consistent with emerging evidence for its function in the central nervous system, including roles in '[Neurogenesis](/details-go/GO:0022008)' and neuronal apoptosis as suggested by functional annotations ([Link](https://doi.org/10.1073/pnas.0335507100)). ## Pathways and Molecular Function The molecular function of [PCSK9](/details-gene/255738) is centered on its role as a key post-translational regulator of lipoprotein receptors. As a '[Serine-type endopeptidase activity](/details-go/GO:0004252)', it is synthesized as a zymogen that undergoes autocatalytic cleavage in the endoplasmic reticulum ([GO:0005783](/https://www.ebi.ac.uk/QuickGO/term/GO:0005783)) before being secreted ([Link](https://doi.org/10.1074/jbc.m606495200)). In the extracellular space, [PCSK9](/details-gene/255738) binds to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR ([GO:0050750](/https://www.ebi.ac.uk/QuickGO/term/GO:0050750)). This interaction prevents the conformational change required for the receptor to release its lipoprotein cargo in the acidic environment of the endosome, thereby shunting the entire PCSK9-LDLR complex to the [lysosome](/details-go/GO:0005764) for degradation ([Link](https://doi.org/10.1111/j.1600-0854.2007.00562.x)). This mechanism is central to the Reactome pathway '[Ldl clearance](/details-reactome/R-HSA-8964038)' and is described by GO terms such as '[Negative regulation of low-density lipoprotein particle clearance](/details-go/GO:0010989)' and '[Positive regulation of low-density lipoprotein particle receptor catabolic process](/details-go/GO:0032805)'. By reducing the number of LDLRs available for recycling to the plasma membrane, [PCSK9](/details-gene/255738) activity leads to increased levels of circulating LDL cholesterol. Beyond LDLR, it can also induce the degradation of other family members like VLDLR and ApoER2 ([Link](https://doi.org/10.1074/jbc.m708098200)). ## Research Directions The well-defined role of [PCSK9](/details-gene/255738) in cholesterol metabolism has made it a successful therapeutic target, but its functions beyond the liver-bloodstream axis remain less understood. The high expression in non-hepatic tissues like the gut and brain suggests pleiotropic roles that warrant further investigation. ### Proposed Hypotheses: 1. **Intestinal-derived [PCSK9](/details-gene/255738) locally regulates dietary lipid absorption and gut microbiome composition.** Given its high significance in [goblet cell](/details-cell/CL0000160) and [colon epithelial cell](/details-cell/CL0011108), intestinal [PCSK9](/details-gene/255738) may act in a paracrine manner to modulate the expression of lipid transporters on enterocytes, thereby influencing the efficiency of cholesterol uptake from the diet. 2. **In the central nervous system, [PCSK9](/details-gene/255738) modulates synaptic plasticity and neuronal survival by controlling local lipoprotein receptor levels.** Its expression in [glial cell](/details-cell/CL0000125) and its annotation in '[Regulation of neuron apoptotic process](/details-go/GO:0043523)' suggest a role in regulating the uptake of essential lipids by neurons, which could be critical during development, in response to injury, or in the context of neurodegenerative diseases. ### Experimental Approach: To test the first hypothesis regarding the local role of intestinal [PCSK9](/details-gene/255738), an intestinal epithelial cell-specific knockout mouse model (e.g., *Pcsk9fl/fl;Villin-Cre*+) could be generated. These mice, alongside littermate controls, would be placed on a high-cholesterol diet. The functional consequences could be assessed by measuring fecal and plasma sterol profiles to determine changes in cholesterol absorption. Furthermore, intestinal organoids derived from these mice could be used to perform transcriptomic (RNA-seq) and proteomic analyses to identify downstream targets of [PCSK9](/details-gene/255738) signaling related to lipid transport and metabolism. ### Therapeutic Potential: [PCSK9](/details-gene/255738) is already a validated and highly successful therapeutic target. Due to its extracellular mode of action, it is an ideal candidate for **inhibition** using biologic drugs. Monoclonal antibodies (e.g., evolocumab, alirocumab) that bind circulating [PCSK9](/details-gene/255738) and prevent its interaction with LDLR are approved therapies for hypercholesterolemia. More recently, RNA interference-based therapies (e.g., inclisiran), which reduce hepatic synthesis of [PCSK9](/details-gene/255738) protein, have also proven effective. The high specificity of these approaches minimizes off-target effects, making [PCSK9](/details-gene/255738) inhibition a cornerstone of modern lipid-lowering therapy.

Genular Protein ID: 794746414

Symbol: PCSK9_HUMAN

Name: Proprotein convertase subtilisin/kexin type 9

UniProtKB Accession Codes:

Q8NBP7 A8T640 C0JYY9 Q5PSM5 Q5SZQ2

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 2 CTD 1 ChEBI 1 ChEMBL 1 ComplexPortal 2 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 3 DrugCentral 1 EC 1 EMBL 9 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 55 Gene3D 3 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MEROPS 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 43 PDBsum 43 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 5 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 Pumba 1 RNAct 1 Reactome 4 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 17971861

Title: Evidence for positive selection in the C-terminal domain of the cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14 primate species.

PubMed ID: 17971861

DOI: 10.1371/journal.pone.0001098

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

PubMed ID: 12552133

Title: The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation.

PubMed ID: 12552133

DOI: 10.1073/pnas.0335507100

PubMed ID: 14622975

Title: Functional characterization of Narc 1, a novel proteinase related to proteinase K.

PubMed ID: 14622975

DOI: 10.1016/j.abb.2003.09.011

PubMed ID: 17081983

Title: Global, in vivo, and site-specific phosphorylation dynamics in signaling networks.

PubMed ID: 17081983

DOI: 10.1016/j.cell.2006.09.026

PubMed ID: 16912035

Title: The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.

PubMed ID: 16912035

DOI: 10.1074/jbc.m606495200

PubMed ID: 17461796

Title: The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR.

PubMed ID: 17461796

DOI: 10.1111/j.1600-0854.2007.00562.x

PubMed ID: 18197702

Title: Self-association of human PCSK9 correlates with its LDLR-degrading activity.

PubMed ID: 18197702

DOI: 10.1021/bi7016359

PubMed ID: 18660751

Title: PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1.

PubMed ID: 18660751

DOI: 10.1038/embor.2008.132

PubMed ID: 18498363

Title: PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans.

PubMed ID: 18498363

DOI: 10.1111/j.1742-4658.2008.06495.x

PubMed ID: 18039658

Title: The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2.

PubMed ID: 18039658

DOI: 10.1074/jbc.m708098200

PubMed ID: 18799458

Title: Annexin A2 is a C-terminal PCSK9-binding protein that regulates endogenous low density lipoprotein receptor levels.

PubMed ID: 18799458

DOI: 10.1074/jbc.m805971200

PubMed ID: 18669648

Title: A quantitative atlas of mitotic phosphorylation.

PubMed ID: 18669648

DOI: 10.1073/pnas.0805139105

PubMed ID: 20068231

Title: Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis.

PubMed ID: 20068231

DOI: 10.1126/scisignal.2000475

PubMed ID: 22074827

Title: Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation.

PubMed ID: 22074827

DOI: 10.1016/j.bbrc.2011.10.110

PubMed ID: 21149300

Title: A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor.

PubMed ID: 21149300

DOI: 10.1074/jbc.m110.199042

PubMed ID: 22027821

Title: Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein.

PubMed ID: 22027821

DOI: 10.1074/jbc.m111.273474

PubMed ID: 21406692

Title: System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation.

PubMed ID: 21406692

DOI: 10.1126/scisignal.2001570

PubMed ID: 22580899

Title: Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor.

PubMed ID: 22580899

DOI: 10.1161/atvbaha.112.250043

PubMed ID: 23186163

Title: Toward a comprehensive characterization of a human cancer cell phosphoproteome.

PubMed ID: 23186163

DOI: 10.1021/pr300630k

PubMed ID: 26091039

Title: A single kinase generates the majority of the secreted phosphoproteome.

PubMed ID: 26091039

DOI: 10.1016/j.cell.2015.05.028

PubMed ID: 18280815

Title: PCSK9: an enigmatic protease.

PubMed ID: 18280815

DOI: 10.1016/j.bbalip.2008.01.003

PubMed ID: 18649882

Title: Molecular basis of PCSK9 function.

PubMed ID: 18649882

DOI: 10.1016/j.atherosclerosis.2008.06.010

PubMed ID: 19930098

Title: The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis.

PubMed ID: 19930098

DOI: 10.1111/j.1365-2796.2009.02167.x

PubMed ID: 19020338

Title: PCSK9: a convertase that coordinates LDL catabolism.

PubMed ID: 19020338

DOI: 10.1194/jlr.r800091-jlr200

PubMed ID: 21943799

Title: Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition.

PubMed ID: 21943799

DOI: 10.1016/j.numecd.2011.06.002

PubMed ID: 19191301

Title: Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease.

PubMed ID: 19191301

DOI: 10.1002/humu.20882

PubMed ID: 22417841

Title: Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients.

PubMed ID: 22417841

DOI: 10.1016/j.atherosclerosis.2012.02.018

PubMed ID: 22493497

Title: Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9).

PubMed ID: 22493497

DOI: 10.1074/jbc.m112.363382

PubMed ID: 24808179

Title: Annexin A2 reduces PCSK9 protein levels via a translational mechanism and interacts with the M1 and M2 domains of PCSK9.

PubMed ID: 24808179

DOI: 10.1074/jbc.m113.541094

PubMed ID: 17502100

Title: The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol.

PubMed ID: 17502100

DOI: 10.1016/j.str.2007.04.004

PubMed ID: 12730697

Title: Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.

PubMed ID: 12730697

DOI: 10.1038/ng1161

PubMed ID: 16465619

Title: A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol.

PubMed ID: 16465619

DOI: 10.1086/500615

PubMed ID: 19319977

Title: The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene.

PubMed ID: 19319977

DOI: 10.1002/humu.21002

PubMed ID: 22095935

Title: Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels.

PubMed ID: 22095935

DOI: 10.1002/humu.21660

Sequence Information:

  • Length: 692
  • Mass: 74286
  • Checksum: 9BCB9418B90AEE23
  • Sequence:
    • MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT 
TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP 
GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV 
EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG 
VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA 
CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD 
LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA 
KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAVARCAPD 
EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP 
PAEASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC 
CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD 
VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ