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Protein

Proprotein convertase subtilisin/kexin type 9

Gene

PCSK9

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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 (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:18799458, PubMed:17461796, PubMed:18197702, 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.8 Publications

Cofactori

Ca2+Curated

Enzyme 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 sitei186Charge relay systemBy similarity1
Active sitei226Charge relay systemBy similarity1
Active sitei386Charge relay systemBy similarity1

GO - Molecular functioni

  • apolipoprotein binding Source: UniProtKB
  • apolipoprotein receptor binding Source: BHF-UCL
  • low-density lipoprotein particle binding Source: UniProtKB
  • low-density lipoprotein particle receptor binding Source: HGNC
  • poly(A) RNA binding Source: UniProtKB
  • protein self-association Source: UniProtKB
  • receptor inhibitor activity Source: BHF-UCL
  • serine-type endopeptidase activity Source: HGNC
  • sodium channel inhibitor activity Source: UniProtKB
  • very-low-density lipoprotein particle binding Source: UniProtKB
  • very-low-density lipoprotein particle receptor binding Source: BHF-UCL

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • cellular response to insulin stimulus Source: HGNC
  • cellular response to starvation Source: HGNC
  • cholesterol homeostasis Source: HGNC
  • cholesterol metabolic process Source: UniProtKB-KW
  • kidney development Source: HGNC
  • lipoprotein metabolic process Source: Ensembl
  • liver development Source: HGNC
  • low-density lipoprotein particle receptor catabolic process Source: UniProtKB
  • lysosomal transport Source: BHF-UCL
  • negative regulation of low-density lipoprotein particle clearance Source: BHF-UCL
  • negative regulation of receptor activity Source: BHF-UCL
  • negative regulation of receptor recycling Source: BHF-UCL
  • negative regulation of sodium ion transmembrane transporter activity Source: BHF-UCL
  • neurogenesis Source: HGNC
  • neuron differentiation Source: HGNC
  • phospholipid metabolic process Source: Ensembl
  • positive regulation of low-density lipoprotein particle receptor catabolic process Source: BHF-UCL
  • positive regulation of neuron apoptotic process Source: HGNC
  • positive regulation of receptor internalization Source: BHF-UCL
  • protein autoprocessing Source: HGNC
  • regulation of neuron apoptotic process Source: UniProtKB
  • regulation of receptor activity Source: BHF-UCL
  • triglyceride metabolic process Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Keywords - Biological processi

Apoptosis, Cholesterol metabolism, Lipid metabolism, Steroid metabolism, Sterol metabolism

Keywords - Ligandi

Calcium

Enzyme and pathway databases

BioCyciZFISH:ENSG00000169174-MONOMER.
BRENDAi3.4.21.61. 2681.
ReactomeiR-HSA-171052. LDL-mediated lipid transport.
R-HSA-8866427. VLDLR internalisation and degradation.
SignaLinkiQ8NBP7.

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
ORF Names:PSEC0052
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:20001. PCSK9.

Subcellular locationi

  • Cytoplasm
  • Secreted
  • Endosome
  • Lysosome
  • Cell surface
  • Endoplasmic reticulum
  • Golgi apparatus

  • 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 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.

GO - Cellular componenti

  • cell surface Source: UniProtKB
  • cytoplasm Source: UniProtKB
  • early endosome Source: UniProtKB
  • endoplasmic reticulum Source: UniProtKB
  • ER to Golgi transport vesicle Source: Ensembl
  • extracellular space Source: HGNC
  • extrinsic component of external side of plasma membrane Source: BHF-UCL
  • Golgi apparatus Source: UniProtKB
  • late endosome Source: UniProtKB
  • lysosome Source: UniProtKB
  • PCSK9-AnxA2 complex Source: BHF-UCL
  • PCSK9-LDLR complex Source: BHF-UCL
  • perinuclear region of cytoplasm Source: BHF-UCL
  • plasma membrane Source: BHF-UCL
  • rough endoplasmic reticulum Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Endoplasmic reticulum, Endosome, Golgi apparatus, Lysosome, Secreted

Pathology & Biotechi

Involvement in diseasei

Hypercholesterolemia, autosomal dominant, 3 (HCHOLA3)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.
See also OMIM:603776
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_017199127S → R in HCHOLA3. 1 PublicationCorresponds to variant rs28942111dbSNPEnsembl.1
Natural variantiVAR_058524129D → G in HCHOLA3. 1
Natural variantiVAR_058526215R → H in HCHOLA3. Corresponds to variant rs794728683dbSNPEnsembl.1
Natural variantiVAR_017200216F → L in HCHOLA3; partial loss of cleavage by furin and PCSK5. 1 PublicationCorresponds to variant rs28942112dbSNPEnsembl.1
Natural variantiVAR_058527218R → S in HCHOLA3; complete loss of cleavage by furin and PCSK5; reduces glycosylation levels; no effect on protein sulfation and phosphorylation; no effect on protein sulfation but inhibits phosphorylation when associated with Y-374; highly reduces LDL uptake when associated with Y-374. 2 Publications1
Natural variantiVAR_058530357R → H in HCHOLA3. Corresponds to variant rs370507566dbSNPEnsembl.1
Natural variantiVAR_058531374D → H in HCHOLA3. 1
Natural variantiVAR_058532374D → Y in HCHOLA3; partial loss of cleavage by furin and PCSK5; no effect on protein sulfation but inhibits phosphorylation when associated with S-218; highly increases LDL uptake when associated with S-218. 2 PublicationsCorresponds to variant rs137852912dbSNPEnsembl.1
Natural variantiVAR_058534496R → W in HCHOLA3. Corresponds to variant rs374603772dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi67C → A: Does not affect multimerization or zymogen processing. 1 Publication1
Mutagenesisi226H → A: Remains in the endoplasmic reticulum and is not secreted. 1 Publication1
Mutagenesisi533N → A: 1.5 kDa decrease of the apparent molecular mass of pro-PCSK9 and PCSK9 and no effect on processing and secretion. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi255738.
MalaCardsiPCSK9.
MIMi603776. phenotype.
OpenTargetsiENSG00000169174.
Orphaneti426. Familial hypobetalipoproteinemia.
406. Heterozygous familial hypercholesterolemia.
391665. Homozygous familial hypercholesterolemia.
PharmGKBiPA38617.

Chemistry databases

ChEMBLiCHEMBL2929.
DrugBankiDB09302. Alirocumab.
DB09303. Evolocumab.
GuidetoPHARMACOLOGYi2388.

Polymorphism and mutation databases

BioMutaiPCSK9.
DMDMi317373487.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 301 PublicationAdd BLAST30
PropeptideiPRO_000002712031 – 1521 PublicationAdd BLAST122
ChainiPRO_0000027121153 – 692Proprotein convertase subtilisin/kexin type 9Add BLAST540

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei38Sulfotyrosine1 Publication1
Modified residuei47Phosphoserine; by FAM20C2 Publications1
Disulfide bondi223 ↔ 255Sequence analysis
Disulfide bondi323 ↔ 358Sequence analysis
Disulfide bondi457 ↔ 527Sequence analysis
Disulfide bondi477 ↔ 526Sequence analysis
Disulfide bondi486 ↔ 509Sequence analysis
Glycosylationi533N-linked (GlcNAc...)1 Publication1
Disulfide bondi534 ↔ 601Sequence analysis
Disulfide bondi552 ↔ 600Sequence analysis
Disulfide bondi562 ↔ 588Sequence analysis
Disulfide bondi608 ↔ 679Sequence analysis
Disulfide bondi626 ↔ 678Sequence analysis
Disulfide bondi635 ↔ 654Sequence analysis
Modified residuei688Phosphoserine; by FAM20CCombined sources2 Publications1

Post-translational modificationi

Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation.
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.1 Publication
Phosphorylation protects the propeptide against proteolysis.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei152 – 153Cleavage; by autolysis2
Sitei218 – 219Cleavage; by furin and PCSK52

Keywords - PTMi

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

Proteomic databases

EPDiQ8NBP7.
MaxQBiQ8NBP7.
PaxDbiQ8NBP7.
PeptideAtlasiQ8NBP7.
PRIDEiQ8NBP7.

PTM databases

iPTMnetiQ8NBP7.
PhosphoSitePlusiQ8NBP7.

Expressioni

Tissue specificityi

Expressed in neuro-epithelioma, colon carcinoma, hepatic and pancreatic cell lines, and in Schwann cells.

Gene expression databases

BgeeiENSG00000169174.
CleanExiHS_PCSK9.
GenevisibleiQ8NBP7. HS.

Organism-specific databases

HPAiCAB025575.

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 (PubMed:18799458).9 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ANXA2P073557EBI-7539251,EBI-352622
LDLRP0113010EBI-7539251,EBI-988319
MMP2P082534EBI-7539251,EBI-1033518

GO - Molecular functioni

  • apolipoprotein binding Source: UniProtKB
  • apolipoprotein receptor binding Source: BHF-UCL
  • low-density lipoprotein particle receptor binding Source: HGNC
  • protein self-association Source: UniProtKB
  • very-low-density lipoprotein particle receptor binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi129116. 26 interactors.
DIPiDIP-29694N.
IntActiQ8NBP7. 4 interactors.
MINTiMINT-3041747.
STRINGi9606.ENSP00000303208.

Chemistry databases

BindingDBiQ8NBP7.

Structurei

Secondary structure

1692
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi63 – 65Combined sources3
Helixi70 – 72Combined sources3
Beta strandi73 – 82Combined sources10
Beta strandi84 – 86Combined sources3
Helixi88 – 104Combined sources17
Beta strandi110 – 115Combined sources6
Beta strandi117 – 119Combined sources3
Beta strandi121 – 125Combined sources5
Helixi128 – 130Combined sources3
Helixi131 – 135Combined sources5
Beta strandi140 – 151Combined sources12
Helixi156 – 160Combined sources5
Helixi168 – 170Combined sources3
Beta strandi181 – 187Combined sources7
Turni194 – 199Combined sources6
Beta strandi200 – 206Combined sources7
Beta strandi212 – 214Combined sources3
Turni218 – 220Combined sources3
Turni221 – 224Combined sources4
Helixi225 – 235Combined sources11
Turni237 – 239Combined sources3
Beta strandi241 – 244Combined sources4
Beta strandi246 – 251Combined sources6
Beta strandi257 – 260Combined sources4
Helixi261 – 277Combined sources17
Beta strandi283 – 287Combined sources5
Beta strandi289 – 292Combined sources4
Helixi295 – 306Combined sources12
Beta strandi310 – 314Combined sources5
Beta strandi317 – 321Combined sources5
Helixi322 – 324Combined sources3
Turni327 – 329Combined sources3
Beta strandi333 – 339Combined sources7
Beta strandi343 – 345Combined sources3
Beta strandi349 – 352Combined sources4
Beta strandi355 – 358Combined sources4
Beta strandi361 – 364Combined sources4
Beta strandi366 – 372Combined sources7
Beta strandi373 – 375Combined sources3
Beta strandi378 – 382Combined sources5
Helixi385 – 402Combined sources18
Helixi408 – 417Combined sources10
Beta strandi419 – 422Combined sources4
Helixi426 – 428Combined sources3
Helixi431 – 433Combined sources3
Turni434 – 436Combined sources3
Beta strandi440 – 442Combined sources3
Beta strandi456 – 461Combined sources6
Beta strandi467 – 470Combined sources4
Beta strandi472 – 475Combined sources4
Beta strandi482 – 489Combined sources8
Beta strandi491 – 493Combined sources3
Beta strandi495 – 503Combined sources9
Beta strandi506 – 513Combined sources8
Beta strandi521 – 528Combined sources8
Beta strandi533 – 539Combined sources7
Beta strandi544 – 546Combined sources3
Beta strandi548 – 551Combined sources4
Beta strandi558 – 565Combined sources8
Beta strandi568 – 570Combined sources3
Beta strandi587 – 590Combined sources4
Beta strandi594 – 602Combined sources9
Beta strandi606 – 615Combined sources10
Beta strandi621 – 625Combined sources5
Beta strandi631 – 637Combined sources7
Beta strandi644 – 650Combined sources7
Beta strandi653 – 658Combined sources6
Beta strandi672 – 681Combined sources10

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2P4EX-ray1.98A/P1-692[»]
2PMWX-ray2.30A31-152[»]
B153-692[»]
2QTWX-ray1.90A29-152[»]
B153-692[»]
2W2MX-ray2.40A153-451[»]
P53-152[»]
2W2NX-ray2.30A153-451[»]
P53-152[»]
2W2OX-ray2.62A153-451[»]
P53-152[»]
2W2PX-ray2.62A153-451[»]
P53-152[»]
2W2QX-ray2.33A153-451[»]
P53-152[»]
2XTJX-ray2.70A153-451[»]
P53-152[»]
3BPSX-ray2.41A153-692[»]
P53-152[»]
3GCWX-ray2.70A153-692[»]
P53-152[»]
3GCXX-ray2.70A153-692[»]
P53-152[»]
3H42X-ray2.30A31-152[»]
B153-692[»]
3M0CX-ray7.01A29-152[»]
B153-692[»]
3P5BX-ray3.30A153-692[»]
P61-152[»]
3P5CX-ray4.20A153-692[»]
P61-152[»]
3SQOX-ray2.70A153-692[»]
P31-152[»]
4K8RX-ray3.22A61-152[»]
B153-692[»]
4NE9X-ray2.60A/B153-692[»]
C/P1-152[»]
4NMXX-ray1.85A31-152[»]
B153-452[»]
4OV6X-ray2.69A/D60-152[»]
B/E153-446[»]
ProteinModelPortaliQ8NBP7.
SMRiQ8NBP7.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ8NBP7.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini182 – 424Peptidase S8Add BLAST243

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni450 – 692C-terminal domainAdd BLAST243

Domaini

The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities.1 Publication
The catalytic domain is responsible for mediating its self-association.1 Publication

Sequence similaritiesi

Belongs to the peptidase S8 family.Curated
Contains 1 peptidase S8 domain.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG1153. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00490000043472.
HOGENOMiHOG000049267.
HOVERGENiHBG053530.
InParanoidiQ8NBP7.
KOiK13050.
OMAiCHAPGLE.
OrthoDBiEOG091G067E.
PhylomeDBiQ8NBP7.
TreeFamiTF106271.

Family and domain databases

Gene3Di3.30.70.80. 1 hit.
3.40.50.200. 1 hit.
InterProiIPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Propept_inh.
IPR010259. S8pro/Inhibitor_I9.
[Graphical view]
PANTHERiPTHR10795. PTHR10795. 1 hit.
PfamiPF05922. Inhibitor_I9. 1 hit.
PF00082. Peptidase_S8. 1 hit.
[Graphical view]
PRINTSiPR00723. SUBTILISIN.
SUPFAMiSSF52743. SSF52743. 1 hit.
SSF54897. SSF54897. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q8NBP7-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED
60 70 80 90 100
GLAEAPEHGT TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA
110 120 130 140 150
QAARRGYLTK ILHVFHGLLP GFLVKMSGDL LELALKLPHV DYIEEDSSVF
160 170 180 190 200
AQSIPWNLER ITPPRYRADE YQPPDGGSLV EVYLLDTSIQ SDHREIEGRV
210 220 230 240 250
MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG VAKGASMRSL
260 270 280 290 300
RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA
310 320 330 340 350
CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT
360 370 380 390 400
LGTNFGRCVD LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML
410 420 430 440 450
SAEPELTLAE LRQRLIHFSA KDVINEAWFP EDQRVLTPNL VAALPPSTHG
460 470 480 490 500
AGWQLFCRTV WSAHSGPTRM ATAVARCAPD EELLSCSSFS RSGKRRGERM
510 520 530 540 550
EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP PAEASMGTRV
560 570 580 590 600
HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC
610 620 630 640 650
CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV
660 670 680 690
DNTCVVRSRD VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ
Length:692
Mass (Da):74,286
Last modified:January 11, 2011 - v3
Checksum:i9BCB9418B90AEE23
GO
Isoform 2 (identifier: Q8NBP7-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-174: MGTVSSRRSW...RYRADEYQPP → MSPWK
     333-365: VITVGATNAQDQPVTLGTLGTNFGRCVDLFAPG → GRTSLVPPATAAPALCHRVGHHRLLPTWLALQP
     366-692: Missing.

Note: No experimental confirmation available.
Show »
Length:196
Mass (Da):20,827
Checksum:i6073DFE87E84FA15
GO

Sequence cautioni

The sequence BAC11572 differs from that shown. Reason: Frameshift at position 494.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti423V → A in BAC11572 (PubMed:14702039).Curated1

Polymorphismi

Variant Leu-23 ins polymorphism in PCSK9 might have a modifier effect on LDLR mutation and familial hypercholesterolemia.
Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIMi:603776].3 Publications

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02133623L → LL This polymoprhism seems to have a modifier effect on LDLR mutation and familial hypercholesterolemia. 4 Publications1
Natural variantiVAR_01719746R → L Polymorphism; associated with lower plasma levels of low-density lipoprotein cholesterol and reduced phosphorylation at Ser-47. 4 PublicationsCorresponds to variant rs11591147dbSNPEnsembl.1
Natural variantiVAR_01719853A → V Polymorphism; associated with reduced phosphorylation at Ser-47. 4 PublicationsCorresponds to variant rs11583680dbSNPEnsembl.1
Natural variantiVAR_02545157E → K.1 PublicationCorresponds to variant rs145886902dbSNPEnsembl.1
Natural variantiVAR_05852077T → I.Corresponds to variant rs756060557dbSNPEnsembl.1
Natural variantiVAR_05852193R → C.Corresponds to variant rs151193009dbSNPEnsembl.1
Natural variantiVAR_058522106G → R.1
Natural variantiVAR_058523114V → A.Corresponds to variant rs775988212dbSNPEnsembl.1
Natural variantiVAR_017199127S → R in HCHOLA3. 1 PublicationCorresponds to variant rs28942111dbSNPEnsembl.1
Natural variantiVAR_058524129D → G in HCHOLA3. 1
Natural variantiVAR_058525157N → K.Corresponds to variant rs143117125dbSNPEnsembl.1
Natural variantiVAR_067351174P → S Found in patients with familial hypercholesterolemia carrying a homozygous LDLR mutation; acts as a disease modifier resulting in a mild phenotype. 1 PublicationCorresponds to variant rs533273863dbSNPEnsembl.1
Natural variantiVAR_058526215R → H in HCHOLA3. Corresponds to variant rs794728683dbSNPEnsembl.1
Natural variantiVAR_017200216F → L in HCHOLA3; partial loss of cleavage by furin and PCSK5. 1 PublicationCorresponds to variant rs28942112dbSNPEnsembl.1
Natural variantiVAR_058527218R → S in HCHOLA3; complete loss of cleavage by furin and PCSK5; reduces glycosylation levels; no effect on protein sulfation and phosphorylation; no effect on protein sulfation but inhibits phosphorylation when associated with Y-374; highly reduces LDL uptake when associated with Y-374. 2 Publications1
Natural variantiVAR_058528219Q → E.Corresponds to variant rs778617372dbSNPEnsembl.1
Natural variantiVAR_025452237R → W.1 PublicationCorresponds to variant rs148195424dbSNPEnsembl.1
Natural variantiVAR_058529239A → D.1
Natural variantiVAR_025453253L → F Polymorphism; associated with lower plasma levels of low-density lipoprotein cholesterol. 1 PublicationCorresponds to variant rs28362270dbSNPEnsembl.1
Natural variantiVAR_058530357R → H in HCHOLA3. Corresponds to variant rs370507566dbSNPEnsembl.1
Natural variantiVAR_058531374D → H in HCHOLA3. 1
Natural variantiVAR_058532374D → Y in HCHOLA3; partial loss of cleavage by furin and PCSK5; no effect on protein sulfation but inhibits phosphorylation when associated with S-218; highly increases LDL uptake when associated with S-218. 2 PublicationsCorresponds to variant rs137852912dbSNPEnsembl.1
Natural variantiVAR_025454391H → N.1 PublicationCorresponds to variant rs146471967dbSNPEnsembl.1
Natural variantiVAR_067282394G → S Found in a patient associated with autosomal dominant hypercholesterolemia; unknown pathological significance. 1 PublicationCorresponds to variant rs368257906dbSNPEnsembl.1
Natural variantiVAR_025455417H → Q.1 PublicationCorresponds to variant rs143275858dbSNPEnsembl.1
Natural variantiVAR_021337425N → S.2 PublicationsCorresponds to variant rs28362261dbSNPEnsembl.1
Natural variantiVAR_021338443A → T Polymorphism; associated with lower plasma levels of low-density lipoprotein cholesterol; more extensive cleavage by furin and PCSK5. 2 PublicationsCorresponds to variant rs28362263dbSNPEnsembl.1
Natural variantiVAR_058533452G → D.1
Natural variantiVAR_025456469R → W.1 PublicationCorresponds to variant rs141502002dbSNPEnsembl.1
Natural variantiVAR_021339474V → I.8 PublicationsCorresponds to variant rs562556dbSNPEnsembl.1
Natural variantiVAR_025457482E → G.1 PublicationCorresponds to variant rs141995194dbSNPEnsembl.1
Natural variantiVAR_073657482E → Q No effect on interaction with ANXA2. 1 Publication1
Natural variantiVAR_058534496R → W in HCHOLA3. Corresponds to variant rs374603772dbSNPEnsembl.1
Natural variantiVAR_025458515F → L.1 Publication1
Natural variantiVAR_058535522A → T.Corresponds to variant rs777300852dbSNPEnsembl.1
Natural variantiVAR_021340553H → R.2 PublicationsCorresponds to variant rs28362270dbSNPEnsembl.1
Natural variantiVAR_025459554Q → E Increases interaction with ANXA2. 2 PublicationsCorresponds to variant rs149311926dbSNPEnsembl.1
Natural variantiVAR_058536616P → L.Corresponds to variant rs755750316dbSNPEnsembl.1
Natural variantiVAR_021341619Q → P.2 PublicationsCorresponds to variant rs28362277dbSNPEnsembl.1
Natural variantiVAR_058537668S → R.Corresponds to variant rs762298323dbSNPEnsembl.1
Natural variantiVAR_017201670G → E.8 PublicationsCorresponds to variant rs505151dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0088441 – 174MGTVS…EYQPP → MSPWK in isoform 2. 1 PublicationAdd BLAST174
Alternative sequenceiVSP_008845333 – 365VITVG…LFAPG → GRTSLVPPATAAPALCHRVG HHRLLPTWLALQP in isoform 2. 1 PublicationAdd BLAST33
Alternative sequenceiVSP_008846366 – 692Missing in isoform 2. 1 PublicationAdd BLAST327

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX127530 mRNA. Translation: CAC38896.1.
EF692496 mRNA. Translation: ABV59216.1.
AK075365 mRNA. Translation: BAC11572.1. Frameshift.
AK124635 mRNA. Translation: BAC85910.1.
AY829011 Genomic DNA. Translation: AAV67948.1.
FJ525880 Genomic DNA. Translation: ACN81318.1.
AL589790, AC091609 Genomic DNA. Translation: CAI17845.1.
CH471059 Genomic DNA. Translation: EAX06660.1.
CCDSiCCDS603.1. [Q8NBP7-1]
RefSeqiNP_777596.2. NM_174936.3. [Q8NBP7-1]
UniGeneiHs.18844.

Genome annotation databases

EnsembliENST00000302118; ENSP00000303208; ENSG00000169174. [Q8NBP7-1]
GeneIDi255738.
KEGGihsa:255738.
UCSCiuc001cyf.3. human. [Q8NBP7-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Web resourcesi

SeattleSNPs

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX127530 mRNA. Translation: CAC38896.1.
EF692496 mRNA. Translation: ABV59216.1.
AK075365 mRNA. Translation: BAC11572.1. Frameshift.
AK124635 mRNA. Translation: BAC85910.1.
AY829011 Genomic DNA. Translation: AAV67948.1.
FJ525880 Genomic DNA. Translation: ACN81318.1.
AL589790, AC091609 Genomic DNA. Translation: CAI17845.1.
CH471059 Genomic DNA. Translation: EAX06660.1.
CCDSiCCDS603.1. [Q8NBP7-1]
RefSeqiNP_777596.2. NM_174936.3. [Q8NBP7-1]
UniGeneiHs.18844.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2P4EX-ray1.98A/P1-692[»]
2PMWX-ray2.30A31-152[»]
B153-692[»]
2QTWX-ray1.90A29-152[»]
B153-692[»]
2W2MX-ray2.40A153-451[»]
P53-152[»]
2W2NX-ray2.30A153-451[»]
P53-152[»]
2W2OX-ray2.62A153-451[»]
P53-152[»]
2W2PX-ray2.62A153-451[»]
P53-152[»]
2W2QX-ray2.33A153-451[»]
P53-152[»]
2XTJX-ray2.70A153-451[»]
P53-152[»]
3BPSX-ray2.41A153-692[»]
P53-152[»]
3GCWX-ray2.70A153-692[»]
P53-152[»]
3GCXX-ray2.70A153-692[»]
P53-152[»]
3H42X-ray2.30A31-152[»]
B153-692[»]
3M0CX-ray7.01A29-152[»]
B153-692[»]
3P5BX-ray3.30A153-692[»]
P61-152[»]
3P5CX-ray4.20A153-692[»]
P61-152[»]
3SQOX-ray2.70A153-692[»]
P31-152[»]
4K8RX-ray3.22A61-152[»]
B153-692[»]
4NE9X-ray2.60A/B153-692[»]
C/P1-152[»]
4NMXX-ray1.85A31-152[»]
B153-452[»]
4OV6X-ray2.69A/D60-152[»]
B/E153-446[»]
ProteinModelPortaliQ8NBP7.
SMRiQ8NBP7.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi129116. 26 interactors.
DIPiDIP-29694N.
IntActiQ8NBP7. 4 interactors.
MINTiMINT-3041747.
STRINGi9606.ENSP00000303208.

Chemistry databases

BindingDBiQ8NBP7.
ChEMBLiCHEMBL2929.
DrugBankiDB09302. Alirocumab.
DB09303. Evolocumab.
GuidetoPHARMACOLOGYi2388.

Protein family/group databases

MEROPSiS08.039.

PTM databases

iPTMnetiQ8NBP7.
PhosphoSitePlusiQ8NBP7.

Polymorphism and mutation databases

BioMutaiPCSK9.
DMDMi317373487.

Proteomic databases

EPDiQ8NBP7.
MaxQBiQ8NBP7.
PaxDbiQ8NBP7.
PeptideAtlasiQ8NBP7.
PRIDEiQ8NBP7.

Protocols and materials databases

DNASUi255738.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000302118; ENSP00000303208; ENSG00000169174. [Q8NBP7-1]
GeneIDi255738.
KEGGihsa:255738.
UCSCiuc001cyf.3. human. [Q8NBP7-1]

Organism-specific databases

CTDi255738.
DisGeNETi255738.
GeneCardsiPCSK9.
GeneReviewsiPCSK9.
H-InvDBHIX0023558.
HGNCiHGNC:20001. PCSK9.
HPAiCAB025575.
MalaCardsiPCSK9.
MIMi603776. phenotype.
607786. gene.
neXtProtiNX_Q8NBP7.
OpenTargetsiENSG00000169174.
Orphaneti426. Familial hypobetalipoproteinemia.
406. Heterozygous familial hypercholesterolemia.
391665. Homozygous familial hypercholesterolemia.
PharmGKBiPA38617.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1153. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00490000043472.
HOGENOMiHOG000049267.
HOVERGENiHBG053530.
InParanoidiQ8NBP7.
KOiK13050.
OMAiCHAPGLE.
OrthoDBiEOG091G067E.
PhylomeDBiQ8NBP7.
TreeFamiTF106271.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000169174-MONOMER.
BRENDAi3.4.21.61. 2681.
ReactomeiR-HSA-171052. LDL-mediated lipid transport.
R-HSA-8866427. VLDLR internalisation and degradation.
SignaLinkiQ8NBP7.

Miscellaneous databases

EvolutionaryTraceiQ8NBP7.
GeneWikiiPCSK9.
GenomeRNAii255738.
PROiQ8NBP7.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000169174.
CleanExiHS_PCSK9.
GenevisibleiQ8NBP7. HS.

Family and domain databases

Gene3Di3.30.70.80. 1 hit.
3.40.50.200. 1 hit.
InterProiIPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Propept_inh.
IPR010259. S8pro/Inhibitor_I9.
[Graphical view]
PANTHERiPTHR10795. PTHR10795. 1 hit.
PfamiPF05922. Inhibitor_I9. 1 hit.
PF00082. Peptidase_S8. 1 hit.
[Graphical view]
PRINTSiPR00723. SUBTILISIN.
SUPFAMiSSF52743. SSF52743. 1 hit.
SSF54897. SSF54897. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiPCSK9_HUMAN
AccessioniPrimary (citable) accession number: Q8NBP7
Secondary accession number(s): A8T640
, C0JYY9, Q5PSM5, Q5SZQ2
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 7, 2003
Last sequence update: January 11, 2011
Last modified: November 2, 2016
This is version 157 of the entry and version 3 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Peptidase families
    Classification of peptidase families and list of entries
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.