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Q8NBP7 (PCSK9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 133. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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 names
Name:PCSK9
Synonyms:NARC1
ORF Names:PSEC0052
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length692 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

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. 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. Ref.12 Ref.13 Ref.14 Ref.16 Ref.19 Ref.23 Ref.31

Cofactor

Calcium Probable.

Enzyme regulation

Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.

Subunit structure

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. Ref.12 Ref.13 Ref.14 Ref.16 Ref.20 Ref.23 Ref.31

Subcellular location

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. Ref.12 Ref.16 Ref.23

Tissue specificity

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 (Ref.21). Ref.21

The catalytic domain is responsible for mediating its self-association. Ref.21

Post-translational modification

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. Ref.9 Ref.11

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.

Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776].

Involvement in disease

Hypercholesterolemia, autosomal dominant, 3 (HCHOLA3) [MIM:603776]: A familial condition characterized by elevated circulating cholesterol contained in either low-density lipoproteins alone or also in very-low-density lipoproteins.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.33

Sequence similarities

Belongs to the peptidase S8 family.

Contains 1 peptidase S8 domain.

Sequence caution

The sequence BAC11572.1 differs from that shown. Reason: Frameshift at position 494.

Ontologies

Keywords
   Biological processApoptosis
Cholesterol metabolism
Lipid metabolism
Steroid metabolism
Sterol metabolism
   Cellular componentCytoplasm
Endoplasmic reticulum
Endosome
Golgi apparatus
Lysosome
Secreted
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainSignal
   LigandCalcium
   Molecular functionHydrolase
Protease
Serine protease
   PTMAutocatalytic cleavage
Disulfide bond
Glycoprotein
Phosphoprotein
Sulfation
Zymogen
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processapoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to insulin stimulus

Inferred from sequence or structural similarity Ref.8. Source: HGNC

cellular response to starvation

Inferred from sequence or structural similarity PubMed 16407292. Source: HGNC

cholesterol homeostasis

Inferred from mutant phenotype PubMed 17170371. Source: HGNC

cholesterol metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

kidney development

Inferred from sequence or structural similarity Ref.8. Source: HGNC

lipoprotein metabolic process

Inferred from electronic annotation. Source: Ensembl

liver development

Inferred from sequence or structural similarity Ref.8. Source: HGNC

low-density lipoprotein particle receptor catabolic process

Inferred from direct assay Ref.13. Source: UniProtKB

lysosomal transport

Inferred from direct assay PubMed 17452316. Source: BHF-UCL

negative regulation of catalytic activity

Inferred from electronic annotation. Source: InterPro

negative regulation of low-density lipoprotein particle clearance

Inferred from direct assay PubMed 17328821. Source: BHF-UCL

negative regulation of receptor recycling

Inferred from direct assay PubMed 17452316. Source: BHF-UCL

neurogenesis

Inferred from sequence or structural similarity Ref.8. Source: HGNC

neuron differentiation

Inferred from sequence or structural similarity Ref.8. Source: HGNC

phospholipid metabolic process

Inferred from electronic annotation. Source: Ensembl

positive regulation of neuron apoptotic process

Inferred from mutant phenotype PubMed 17051583. Source: HGNC

positive regulation of receptor internalization

Inferred from direct assay PubMed 17328821. Source: BHF-UCL

protein autoprocessing

Inferred from direct assay Ref.9. Source: HGNC

proteolysis

Inferred from Biological aspect of Ancestor. Source: RefGenome

regulation of low-density lipoprotein particle receptor catabolic process

Inferred from electronic annotation. Source: Ensembl

regulation of neuron apoptotic process

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of receptor activity

Inferred from direct assay PubMed 17328821. Source: BHF-UCL

triglyceride metabolic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentGolgi apparatus

Inferred from direct assay Ref.12. Source: UniProtKB

cell surface

Inferred from direct assay Ref.12. Source: UniProtKB

cytoplasm

Inferred from direct assay Ref.23. Source: UniProtKB

early endosome

Inferred from direct assay Ref.12. Source: UniProtKB

endoplasmic reticulum

Inferred from direct assay Ref.12. Source: UniProtKB

extracellular space

Inferred from direct assay Ref.8Ref.11PubMed 17080197. Source: HGNC

extrinsic component of external side of plasma membrane

Inferred by curator PubMed 17328821. Source: BHF-UCL

late endosome

Inferred from direct assay Ref.12. Source: UniProtKB

lysosome

Inferred from direct assay Ref.12. Source: UniProtKB

perinuclear region of cytoplasm

Inferred from direct assay Ref.16. Source: BHF-UCL

rough endoplasmic reticulum

Inferred from electronic annotation. Source: Ensembl

   Molecular_functionapolipoprotein binding

Inferred from sequence or structural similarity. Source: UniProtKB

apolipoprotein receptor binding

Inferred from direct assay Ref.16. Source: BHF-UCL

low-density lipoprotein particle binding

Inferred from sequence or structural similarity. Source: UniProtKB

low-density lipoprotein particle receptor binding

Inferred from direct assay PubMed 17080197. Source: HGNC

poly(A) RNA binding

Inferred from direct assay PubMed 22658674. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.12Ref.31Ref.23. Source: UniProtKB

protein self-association

Inferred from direct assay Ref.13. Source: UniProtKB

serine-type endopeptidase activity

Inferred from direct assay Ref.8. Source: HGNC

sodium channel inhibitor activity

Inferred from direct assay Ref.31. Source: UniProtKB

very-low-density lipoprotein particle binding

Inferred from sequence or structural similarity. Source: UniProtKB

very-low-density lipoprotein particle receptor binding

Inferred from direct assay Ref.16. Source: BHF-UCL

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

LDLRP011309EBI-7539251,EBI-988319

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q8NBP7-1)

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.
Isoform 2 (identifier: Q8NBP7-2)

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.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 3030 Ref.8
Propeptide31 – 152122
PRO_0000027120
Chain153 – 692540Proprotein convertase subtilisin/kexin type 9
PRO_0000027121

Regions

Domain161 – 431271Peptidase S8
Region153 – 449297Catalytic domain
Region450 – 692243C-terminal domain

Sites

Active site1861Charge relay system By similarity
Active site2261Charge relay system By similarity
Active site3861Charge relay system By similarity
Site152 – 1532Cleavage; by autolysis
Site218 – 2192Cleavage; by furin and PCSK5

Amino acid modifications

Modified residue381Sulfotyrosine Ref.11
Modified residue471Phosphoserine Ref.15
Modified residue6881Phosphoserine Ref.10 Ref.15 Ref.18 Ref.22
Glycosylation5331N-linked (GlcNAc...) Ref.11
Disulfide bond223 ↔ 255 Potential
Disulfide bond323 ↔ 358 Potential
Disulfide bond457 ↔ 527 Potential
Disulfide bond477 ↔ 526 Potential
Disulfide bond486 ↔ 509 Potential
Disulfide bond534 ↔ 601 Potential
Disulfide bond552 ↔ 600 Potential
Disulfide bond562 ↔ 588 Potential
Disulfide bond608 ↔ 679 Potential
Disulfide bond626 ↔ 678 Potential
Disulfide bond635 ↔ 654 Potential

Natural variations

Alternative sequence1 – 174174MGTVS…EYQPP → MSPWK in isoform 2.
VSP_008844
Alternative sequence333 – 36533VITVG…LFAPG → GRTSLVPPATAAPALCHRVG HHRLLPTWLALQP in isoform 2.
VSP_008845
Alternative sequence366 – 692327Missing in isoform 2.
VSP_008846
Natural variant231L → LL This polymoprhism seems to have a modifier effect on LDLR mutation and familial hypercholesterolemia. Ref.4 Ref.5 Ref.35 Ref.36
VAR_021336
Natural variant461R → L Polymorphism associated with lower plasma levels of low-density lipoprotein cholesterol and reduced phosphorylation at Ser-47. Ref.4 Ref.33 Ref.34 Ref.36
Corresponds to variant rs11591147 [ dbSNP | Ensembl ].
VAR_017197
Natural variant531A → V Polymorphism associated with reduced phosphorylation at Ser-47. Ref.4 Ref.33 Ref.34 Ref.36
Corresponds to variant rs11583680 [ dbSNP | Ensembl ].
VAR_017198
Natural variant571E → K. Ref.34
VAR_025451
Natural variant771T → I.
VAR_058520
Natural variant931R → C.
Corresponds to variant rs151193009 [ dbSNP | Ensembl ].
VAR_058521
Natural variant1061G → R.
VAR_058522
Natural variant1141V → A.
VAR_058523
Natural variant1271S → R in HCHOLA3. Ref.33
Corresponds to variant rs28942111 [ dbSNP | Ensembl ].
VAR_017199
Natural variant1291D → G in HCHOLA3.
VAR_058524
Natural variant1571N → K.
VAR_058525
Natural variant1741P → S Found in patients with familial hypercholesterolemia carrying a homozygous LDLR mutation; acts as a disease modifier resulting in a mild phenotype. Ref.30
VAR_067351
Natural variant2151R → H in HCHOLA3.
VAR_058526
Natural variant2161F → L in HCHOLA3; partial loss of cleavage by furin and PCSK5. Ref.33
Corresponds to variant rs28942112 [ dbSNP | Ensembl ].
VAR_017200
Natural variant2181R → S in HCHOLA3; complete loss of cleavage by furin and PCSK5.
VAR_058527
Natural variant2191Q → E.
VAR_058528
Natural variant2371R → W. Ref.34
VAR_025452
Natural variant2391A → D.
VAR_058529
Natural variant2531L → F Polymorphism associated with lower plasma levels of low-density lipoprotein cholesterol. Ref.34
Corresponds to variant rs28362270 [ dbSNP | Ensembl ].
VAR_025453
Natural variant3571R → H in HCHOLA3.
VAR_058530
Natural variant3741D → H in HCHOLA3.
VAR_058531
Natural variant3741D → Y in HCHOLA3; partial loss of cleavage by furin and PCSK5.
VAR_058532
Natural variant3911H → N. Ref.34
VAR_025454
Natural variant3941G → S Found in a patient associated with autosomal dominant hypercholesterolemia; unknown pathological significance. Ref.36
VAR_067282
Natural variant4171H → Q. Ref.34
Corresponds to variant rs143275858 [ dbSNP | Ensembl ].
VAR_025455
Natural variant4251N → S. Ref.4 Ref.34
Corresponds to variant rs28362261 [ dbSNP | Ensembl ].
VAR_021337
Natural variant4431A → T Polymorphism associated with lower plasma levels of low-density lipoprotein cholesterol; more extensive cleavage by furin and PCSK5. Ref.4 Ref.34
Corresponds to variant rs28362263 [ dbSNP | Ensembl ].
VAR_021338
Natural variant4521G → D.
VAR_058533
Natural variant4691R → W. Ref.34
Corresponds to variant rs141502002 [ dbSNP | Ensembl ].
VAR_025456
Natural variant4741V → I. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.7 Ref.34 Ref.36
Corresponds to variant rs562556 [ dbSNP | Ensembl ].
VAR_021339
Natural variant4821E → G. Ref.34
VAR_025457
Natural variant4961R → W in HCHOLA3.
VAR_058534
Natural variant5151F → L. Ref.34
VAR_025458
Natural variant5221A → T.
VAR_058535
Natural variant5531H → R. Ref.4 Ref.34
Corresponds to variant rs28362270 [ dbSNP | Ensembl ].
VAR_021340
Natural variant5541Q → E. Ref.34
Corresponds to variant rs149311926 [ dbSNP | Ensembl ].
VAR_025459
Natural variant6161P → L.
VAR_058536
Natural variant6191Q → P. Ref.4 Ref.34
Corresponds to variant rs28362277 [ dbSNP | Ensembl ].
VAR_021341
Natural variant6681S → R.
VAR_058537
Natural variant6701G → E. Ref.1 Ref.2 Ref.4 Ref.5 Ref.7 Ref.33 Ref.34 Ref.36
Corresponds to variant rs505151 [ dbSNP | Ensembl ].
VAR_017201

Experimental info

Mutagenesis671C → A: Does not affect multimerization or zymogen processing. Ref.8
Mutagenesis2261H → A: Remains in the endoplasmic reticulum and is not secreted. Ref.8
Mutagenesis5331N → A: 1.5 kDa decrease of the apparent molecular mass of pro-PCSK9 and PCSK9 and no effect on processing and secretion. Ref.8
Sequence conflict4231V → A in BAC11572. Ref.3

Secondary structure

.............................................................................................................................. 692
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified January 11, 2011. Version 3.
Checksum: 9BCB9418B90AEE23

FASTA69274,286
        10         20         30         40         50         60 
MGTVSSRRSW WPLPLLLLLL LLLGPAGARA QEDEDGDYEE LVLALRSEED GLAEAPEHGT 

        70         80         90        100        110        120 
TATFHRCAKD PWRLPGTYVV VLKEETHLSQ SERTARRLQA QAARRGYLTK ILHVFHGLLP 

       130        140        150        160        170        180 
GFLVKMSGDL LELALKLPHV DYIEEDSSVF AQSIPWNLER ITPPRYRADE YQPPDGGSLV 

       190        200        210        220        230        240 
EVYLLDTSIQ SDHREIEGRV MVTDFENVPE EDGTRFHRQA SKCDSHGTHL AGVVSGRDAG 

       250        260        270        280        290        300 
VAKGASMRSL RVLNCQGKGT VSGTLIGLEF IRKSQLVQPV GPLVVLLPLA GGYSRVLNAA 

       310        320        330        340        350        360 
CQRLARAGVV LVTAAGNFRD DACLYSPASA PEVITVGATN AQDQPVTLGT LGTNFGRCVD 

       370        380        390        400        410        420 
LFAPGEDIIG ASSDCSTCFV SQSGTSQAAA HVAGIAAMML SAEPELTLAE LRQRLIHFSA 

       430        440        450        460        470        480 
KDVINEAWFP EDQRVLTPNL VAALPPSTHG AGWQLFCRTV WSAHSGPTRM ATAVARCAPD 

       490        500        510        520        530        540 
EELLSCSSFS RSGKRRGERM EAQGGKLVCR AHNAFGGEGV YAIARCCLLP QANCSVHTAP 

       550        560        570        580        590        600 
PAEASMGTRV HCHQQGHVLT GCSSHWEVED LGTHKPPVLR PRGQPNQCVG HREASIHASC 

       610        620        630        640        650        660 
CHAPGLECKV KEHGIPAPQE QVTVACEEGW TLTGCSALPG TSHVLGAYAV DNTCVVRSRD 

       670        680        690 
VSTTGSTSEG AVTAVAICCR SRHLAQASQE LQ 

« Hide

Isoform 2 [UniParc].

Checksum: 6073DFE87E84FA15
Show »

FASTA19620,827

References

« Hide 'large scale' references
[1]"Nucleic acid molecules derived from rat brain and programmed cell death models."
Chiang L.W.
Patent number WO0131007, 03-MAY-2001
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS ILE-474 AND GLU-670.
[2]"Evidence for positive selection in the C-terminal domain of the cholesterol metabolism gene PCSK9 based on phylogenetic analysis in 14 primate species."
Ding K., McDonough S.J., Kullo I.J.
PLoS ONE 2:E1098-E1098(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS ILE-474 AND GLU-670.
[3]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), VARIANT ILE-474.
Tissue: Cerebellum and Teratocarcinoma.
[4]SeattleSNPs variation discovery resource
Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-23 INS; LEU-46; VAL-53; SER-425; THR-443; ILE-474; ARG-553; PRO-619 AND GLU-670.
[5]NHLBI resequencing and genotyping service (RS&G)
Submitted (DEC-2008) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-23 INS; ILE-474 AND GLU-670.
[6]"The DNA sequence and biological annotation of human chromosome 1."
Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. expand/collapse author list , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.
Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANTS ILE-474 AND GLU-670.
[8]"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation."
Seidah N.G., Benjannet S., Wickham L., Marcinkiewicz J., Jasmin S.B., Stifani S., Basak A., Prat A., Chretien M.
Proc. Natl. Acad. Sci. U.S.A. 100:928-933(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEIN SEQUENCE OF N-TERMINUS, CHARACTERIZATION, MUTAGENESIS OF CYS-67; HIS-226 AND ASN-533.
[9]"Functional characterization of Narc 1, a novel proteinase related to proteinase K."
Naureckiene S., Ma L., Sreekumar K., Purandare U., Lo C.F., Huang Y., Chiang L.W., Grenier J.M., Ozenberger B.A., Jacobsen J.S., Kennedy J.D., DiStefano P.S., Wood A., Bingham B.
Arch. Biochem. Biophys. 420:55-67(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: AUTOCATALYTIC CLEAVAGE SITE.
[10]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[11]"The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications."
Benjannet S., Rhainds D., Hamelin J., Nassoury N., Seidah N.G.
J. Biol. Chem. 281:30561-30572(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION AT ASN-533, SULFATION AT TYR-38, CLEAVAGE AT ARG-218 BY FURIN AND PCSK5.
[12]"The cellular trafficking of the secretory proprotein convertase PCSK9 and its dependence on the LDLR."
Nassoury N., Blasiole D.A., Tebon Oler A., Benjannet S., Hamelin J., Poupon V., McPherson P.S., Attie A.D., Prat A., Seidah N.G.
Traffic 8:718-732(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH LDLR.
[13]"Self-association of human PCSK9 correlates with its LDLR-degrading activity."
Fan D., Yancey P.G., Qiu S., Ding L., Weeber E.J., Linton M.F., Fazio S.
Biochemistry 47:1631-1639(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBUNIT.
[14]"PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1."
Jonas M.C., Costantini C., Puglielli L.
EMBO Rep. 9:916-922(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH BACE1.
[15]"PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans."
Dewpura T., Raymond A., Hamelin J., Seidah N.G., Mbikay M., Chretien M., Mayne J.
FEBS J. 275:3480-3493(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION AT SER-47 AND SER-688, IDENTIFICATION BY MASS SPECTROMETRY.
[16]"The proprotein convertase PCSK9 induces the degradation of low density lipoprotein receptor (LDLR) and its closest family members VLDLR and ApoER2."
Poirier S., Mayer G., Benjannet S., Bergeron E., Marcinkiewicz J., Nassoury N., Mayer H., Nimpf J., Prat A., Seidah N.G.
J. Biol. Chem. 283:2363-2372(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH VLDLR AND LRP8/APOER2.
[17]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[18]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[19]"Role of ubiquitination in PCSK9-mediated low-density lipoprotein receptor degradation."
Chen Y., Wang H., Yu L., Yu X., Qian Y.W., Cao G., Wang J.
Biochem. Biophys. Res. Commun. 415:515-518(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[20]"A two-step binding model of PCSK9 interaction with the low density lipoprotein receptor."
Yamamoto T., Lu C., Ryan R.O.
J. Biol. Chem. 286:5464-5470(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH LDLR.
[21]"Novel domain interaction regulates secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) protein."
Du F., Hui Y., Zhang M., Linton M.F., Fazio S., Fan D.
J. Biol. Chem. 286:43054-43061(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: DOMAIN C-TERMINAL.
[22]"System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation."
Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.
Sci. Signal. 4:RS3-RS3(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-688, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[23]"Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor."
Sun H., Samarghandi A., Zhang N., Yao Z., Xiong M., Teng B.B.
Arterioscler. Thromb. Vasc. Biol. 32:1585-1595(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH APOB.
[24]"PCSK9: an enigmatic protease."
Lopez D.
Biochim. Biophys. Acta 1781:184-191(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[25]"Molecular basis of PCSK9 function."
Lambert G., Charlton F., Rye K.A., Piper D.E.
Atherosclerosis 203:1-7(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[26]"The unique role of proprotein convertase subtilisin/kexin 9 in cholesterol homeostasis."
Mousavi S.A., Berge K.E., Leren T.P.
J. Intern. Med. 266:507-519(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[27]"PCSK9: a convertase that coordinates LDL catabolism."
Horton J.D., Cohen J.C., Hobbs H.H.
J. Lipid Res. 50:S172-S177(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[28]"Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition."
Tibolla G., Norata G.D., Artali R., Meneghetti F., Catapano A.L.
Nutr. Metab. Cardiovasc. Dis. 21:835-843(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW.
[29]"Mutations and polymorphisms in the proprotein convertase subtilisin kexin 9 (PCSK9) gene in cholesterol metabolism and disease."
Abifadel M., Rabes J.P., Devillers M., Munnich A., Erlich D., Junien C., Varret M., Boileau C.
Hum. Mutat. 30:520-529(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: REVIEW ON VARIANTS.
[30]"Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients."
Slimani A., Jelassi A., Jguirim I., Najah M., Rebhi L., Omezzine A., Maatouk F., Hamda K.B., Kacem M., Rabes J.P., Abifadel M., Boileau C., Rouis M., Slimane M.N., Varret M.
Atherosclerosis 222:158-166(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN LDLCQ1, VARIANT SER-174.
[31]"Regulation of epithelial sodium channel trafficking by proprotein convertase subtilisin/kexin type 9 (PCSK9)."
Sharotri V., Collier D.M., Olson D.R., Zhou R., Snyder P.M.
J. Biol. Chem. 287:19266-19274(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH SCNN1A; SCNN1B AND SCNN1G.
[32]"The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol."
Piper D.E., Jackson S., Liu Q., Romanow W.G., Shetterly S., Thibault S.T., Shan B., Walker N.P.
Structure 15:545-552(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 31-692.
[33]"Mutations in PCSK9 cause autosomal dominant hypercholesterolemia."
Abifadel M., Varret M., Rabes J.-P., Allard D., Ouguerram K., Devillers M., Cruaud C., Benjannet S., Wickham L., Erlich D., Derre A., Villeger L., Farnier M., Beucler I., Bruckert E., Chambaz J., Chanu B., Lecerf J.-M. expand/collapse author list , Luc G., Moulin P., Weissenbach J., Prat A., Krempf M., Junien C., Seidah N.G., Boileau C.
Nat. Genet. 34:154-156(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS HCHOLA3 ARG-127 AND LEU-216, VARIANTS LEU-46; VAL-53 AND GLU-670.
[34]"A spectrum of PCSK9 alleles contributes to plasma levels of low-density lipoprotein cholesterol."
Kotowski I.K., Pertsemlidis A., Luke A., Cooper R.S., Vega G.L., Cohen J.C., Hobbs H.H.
Am. J. Hum. Genet. 78:410-422(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS LEU-46; VAL-53; LYS-57; TRP-237; PHE-253; ASN-391; GLN-417; SER-425; THR-443; TRP-469; ILE-474; GLY-482; LEU-515; ARG-553; GLU-554; PRO-619 AND GLU-670.
[35]"The molecular basis of familial hypercholesterolemia in Lebanon: spectrum of LDLR mutations and role of PCSK9 as a modifier gene."
Abifadel M., Rabes J.-P., Jambart S., Halaby G., Gannage-Yared M.-H., Sarkis A., Beaino G., Varret M., Salem N., Corbani S., Aydenian H., Junien C., Munnich A., Boileau C.
Hum. Mutat. 30:E682-E691(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN LDLCQ1, VARIANT LEU-23 INS, IMPACT ON FAMILIAL HYPERCHOLESTEROLEMIA.
[36]"Genetic variation in APOB, PCSK9, and ANGPTL3 in carriers of pathogenic autosomal dominant hypercholesterolemic mutations with unexpected low LDL-Cl Levels."
Huijgen R., Sjouke B., Vis K., de Randamie J.S., Defesche J.C., Kastelein J.J., Hovingh G.K., Fouchier S.W.
Hum. Mutat. 33:448-455(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN LDLCQ1, VARIANTS LEU-23 INS; LEU-46; VAL-53; SER-394; ILE-474 AND GLU-670.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS603.1. [Q8NBP7-1]
RefSeqNP_777596.2. NM_174936.3. [Q8NBP7-1]
UniGeneHs.18844.

3D structure databases

PDBe
RCSB-PDB
PDBj
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[»]
4NMXX-ray1.85A31-152[»]
B153-452[»]
ProteinModelPortalQ8NBP7.
SMRQ8NBP7. Positions 61-682.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid129116. 2 interactions.
DIPDIP-29694N.
IntActQ8NBP7. 1 interaction.
MINTMINT-3041747.
STRING9606.ENSP00000303208.

Chemistry

BindingDBQ8NBP7.
ChEMBLCHEMBL2929.

Protein family/group databases

MEROPSS08.039.

PTM databases

PhosphoSiteQ8NBP7.

Polymorphism databases

DMDM317373487.

Proteomic databases

MaxQBQ8NBP7.
PaxDbQ8NBP7.
PRIDEQ8NBP7.

Protocols and materials databases

DNASU255738.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000302118; ENSP00000303208; ENSG00000169174. [Q8NBP7-1]
GeneID255738.
KEGGhsa:255738.
UCSCuc001cyf.2. human. [Q8NBP7-1]

Organism-specific databases

CTD255738.
GeneCardsGC01P055505.
GeneReviewsPCSK9.
H-InvDBHIX0023558.
HGNCHGNC:20001. PCSK9.
HPACAB025575.
MIM603776. phenotype.
607786. gene.
neXtProtNX_Q8NBP7.
Orphanet426. Familial hypobetalipoproteinemia.
406. Heterozygous familial hypercholesterolemia.
391665. Homozygous familial hypercholesterolemia.
PharmGKBPA38617.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG1404.
HOGENOMHOG000049267.
HOVERGENHBG053530.
InParanoidQ8NBP7.
KOK13050.
OMAHVLTGCS.
OrthoDBEOG79PJNT.
PhylomeDBQ8NBP7.
TreeFamTF106271.

Enzyme and pathway databases

SignaLinkQ8NBP7.

Gene expression databases

ArrayExpressQ8NBP7.
BgeeQ8NBP7.
CleanExHS_PCSK9.
GenevestigatorQ8NBP7.

Family and domain databases

Gene3D3.40.50.200. 1 hit.
InterProIPR010259. Inhibitor_I9.
IPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Prot_inh_propept.
[Graphical view]
PANTHERPTHR10795. PTHR10795. 1 hit.
PfamPF05922. Inhibitor_I9. 1 hit.
PF00082. Peptidase_S8. 1 hit.
[Graphical view]
PRINTSPR00723. SUBTILISIN.
SUPFAMSSF52743. SSF52743. 1 hit.
SSF54897. SSF54897. 1 hit.
ProtoNetSearch...

Other

EvolutionaryTraceQ8NBP7.
GeneWikiPCSK9.
GenomeRNAi255738.
NextBio92626.
PROQ8NBP7.
SOURCESearch...

Entry information

Entry namePCSK9_HUMAN
AccessionPrimary (citable) accession number: Q8NBP7
Secondary accession number(s): A8T640 expand/collapse secondary AC list , C0JYY9, Q5PSM5, Q5SZQ2
Entry history
Integrated into UniProtKB/Swiss-Prot: November 7, 2003
Last sequence update: January 11, 2011
Last modified: July 9, 2014
This is version 133 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM