Q8NBP7 (PCSK9_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	PCSK9
Synonyms:	NARC1
ORF Names:	PSEC0052

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	692 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 co-localizes 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 process	Apoptosis Cholesterol metabolism Lipid metabolism Steroid metabolism Sterol metabolism
Cellular component	Cytoplasm Endoplasmic reticulum Endosome Golgi apparatus Lysosome Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Autocatalytic cleavage Disulfide bond Glycoprotein Phosphoprotein Sulfation Zymogen
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic 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 induction of apoptosis Inferred from electronic annotation. Source: Compara kidney development Inferred from sequence or structural similarity Ref.8. Source: HGNC lipoprotein metabolic process Inferred from electronic annotation. Source: Compara 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 neuron differentiation Inferred from sequence or structural similarity Ref.8. Source: HGNC phospholipid metabolic process Inferred from electronic annotation. Source: Compara 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: Compara regulation of receptor activity Inferred from direct assay PubMed 17328821. Source: BHF-UCL triglyceride metabolic process Inferred from electronic annotation. Source: Compara
Cellular_component	Golgi apparatus Inferred from direct assay Ref.12. 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 to 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: Compara
Molecular_function	apolipoprotein 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 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...

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 30

30

Ref.8

Propeptide

31 – 152

122

PRO_0000027120

Chain

153 – 692

540

Proprotein convertase subtilisin/kexin type 9

PRO_0000027121

Regions

Domain

161 – 431

271

Peptidase S8

Region

153 – 449

297

Catalytic domain

Region

450 – 692

243

C-terminal domain

Sites

Active site

186

1

Charge relay system By similarity

Active site

226

1

Charge relay system By similarity

Active site

386

1

Charge relay system By similarity

Site

152 – 153

2

Cleavage; by autolysis

Site

218 – 219

2

Cleavage; by furin and PCSK5

Amino acid modifications

Modified residue

38

1

Sulfotyrosine Ref.11

Modified residue

47

1

Phosphoserine Ref.15

Modified residue

688

1

Phosphoserine Ref.10 Ref.15 Ref.18 Ref.22

Glycosylation

533

1

N-linked (GlcNAc...) Ref.11

Disulfide bond

223 ↔ 255

Potential

Disulfide bond

323 ↔ 358

Potential

Disulfide bond

457 ↔ 527

Potential

Disulfide bond

477 ↔ 526

Potential

Disulfide bond

486 ↔ 509

Potential

Disulfide bond

534 ↔ 601

Potential

Disulfide bond

552 ↔ 600

Potential

Disulfide bond

562 ↔ 588

Potential

Disulfide bond

608 ↔ 679

Potential

Disulfide bond

626 ↔ 678

Potential

Disulfide bond

635 ↔ 654

Potential

Natural variations

Alternative sequence

1 – 174

174

MGTVS…EYQPP → MSPWK in isoform 2.

VSP_008844

Alternative sequence

333 – 365

33

VITVG…LFAPG → GRTSLVPPATAAPALCHRVG HHRLLPTWLALQP in isoform 2.

VSP_008845

Alternative sequence

366 – 692

327

Missing in isoform 2.

VSP_008846

Natural variant

23

1

L → 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 variant

46

1

R → 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 variant

53

1

A → 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 variant

57

1

E → K. Ref.34

VAR_025451

Natural variant

77

1

T → I.

VAR_058520

Natural variant

93

1

R → C.

VAR_058521

Natural variant

106

1

G → R.

VAR_058522

Natural variant

114

1

V → A.

VAR_058523

Natural variant

127

1

S → R in HCHOLA3. Ref.33
Corresponds to variant rs28942111 [ dbSNP | Ensembl ].

VAR_017199

Natural variant

129

1

D → G in HCHOLA3.

VAR_058524

Natural variant

157

1

N → K.

VAR_058525

Natural variant

174

1

P → 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 variant

215

1

R → H in HCHOLA3.

VAR_058526

Natural variant

216

1

F → L in HCHOLA3; partial loss of cleavage by furin and PCSK5. Ref.33
Corresponds to variant rs28942112 [ dbSNP | Ensembl ].

VAR_017200

Natural variant

218

1

R → S in HCHOLA3; complete loss of cleavage by furin and PCSK5.

VAR_058527

Natural variant

219

1

Q → E.

VAR_058528

Natural variant

237

1

R → W. Ref.34

VAR_025452

Natural variant

239

1

A → D.

VAR_058529

Natural variant

253

1

L → F Polymorphism associated with lower plasma levels of low-density lipoprotein cholesterol. Ref.34
Corresponds to variant rs28362270 [ dbSNP | Ensembl ].

VAR_025453

Natural variant

357

1

R → H in HCHOLA3.

VAR_058530

Natural variant

374

1

D → H in HCHOLA3.

VAR_058531

Natural variant

374

1

D → Y in HCHOLA3; partial loss of cleavage by furin and PCSK5.

VAR_058532

Natural variant

391

1

H → N. Ref.34

VAR_025454

Natural variant

394

1

G → S Found in a patient associated with autosomal dominant hypercholesterolemia; unknown pathological significance. Ref.36

VAR_067282

Natural variant

417

1

H → Q. Ref.34

VAR_025455

Natural variant

425

1

N → S. Ref.4 Ref.34
Corresponds to variant rs28362261 [ dbSNP | Ensembl ].

VAR_021337

Natural variant

443

1

A → 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 variant

452

1

G → D.

VAR_058533

Natural variant

469

1

R → W. Ref.34

VAR_025456

Natural variant

474

1

V → 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 variant

482

1

E → G. Ref.34

VAR_025457

Natural variant

496

1

R → W in HCHOLA3.

VAR_058534

Natural variant

515

1

F → L. Ref.34

VAR_025458

Natural variant

522

1

A → T.

VAR_058535

Natural variant

553

1

H → R. Ref.4 Ref.34
Corresponds to variant rs28362270 [ dbSNP | Ensembl ].

VAR_021340

Natural variant

554

1

Q → E. Ref.34

VAR_025459

Natural variant

616

1

P → L.

VAR_058536

Natural variant

619

1

Q → P. Ref.4 Ref.34
Corresponds to variant rs28362277 [ dbSNP | Ensembl ].

VAR_021341

Natural variant

668

1

S → R.

VAR_058537

Natural variant

670

1

G → 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

Mutagenesis

67

1

C → A: Does not affect multimerization or zymogen processing. Ref.8

Mutagenesis

226

1

H → A: Remains in the endoplasmic reticulum and is not secreted. Ref.8

Mutagenesis

533

1

N → 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 conflict

423

1

V → A in BAC11572. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

692

Helix Strand Turn

Details...

Beta strand

63 – 65

3

Helix

70 – 72

3

Beta strand

73 – 82

10

Helix

88 – 104

17

Beta strand

110 – 115

6

Beta strand

117 – 119

3

Beta strand

121 – 125

5

Helix

128 – 130

3

Helix

131 – 135

5

Beta strand

140 – 151

12

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified January 11, 2011. Version 3. Checksum: 9BCB9418B90AEE23	FASTA	692	74,286
	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
	Isoform 2 [UniParc]. Checksum: 6073DFE87E84FA15	FASTA	196	20,827
	10 20 30 40 50 60 MSPWKDGGSL VEVYLLDTSI QSDHREIEGR VMVTDFENVP EEDGTRFHRQ ASKCDSHGTH 70 80 90 100 110 120 LAGVVSGRDA GVAKGASMRS LRVLNCQGKG TVSGTLIGLE FIRKSQLVQP VGPLVVLLPL 130 140 150 160 170 180 AGGYSRVLNA ACQRLARAGV VLVTAAGNFR DDACLYSPAS APEGRTSLVP PATAAPALCH 190 RVGHHRLLPT WLALQP

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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, MASS SPECTROMETRY. 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, 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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY.
[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. , 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

SeattleSNPs

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.

IPI

IPI00387168.
IPI00387169.

RefSeq

NP_777596.2. NM_174936.3.

UniGene

Hs.18844.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2P4E	X-ray	1.98	A/P	1-692	[»]
2PMW	X-ray	2.30	A	31-152	[»]
			B	153-692	[»]
2QTW	X-ray	1.90	A	29-152	[»]
			B	153-692	[»]
2W2M	X-ray	2.40	A	153-451	[»]
			P	53-152	[»]
2W2N	X-ray	2.30	A	153-451	[»]
			P	53-152	[»]
2W2O	X-ray	2.62	A	153-451	[»]
			P	53-152	[»]
2W2P	X-ray	2.62	A	153-451	[»]
			P	53-152	[»]
2W2Q	X-ray	2.33	A	153-451	[»]
			P	53-152	[»]
2XTJ	X-ray	2.70	A	153-451	[»]
			P	53-152	[»]
3BPS	X-ray	2.41	A	153-692	[»]
			P	53-152	[»]
3GCW	X-ray	2.70	A	153-692	[»]
			P	53-152	[»]
3GCX	X-ray	2.70	A	153-692	[»]
			P	53-152	[»]
3H42	X-ray	2.30	A	31-152	[»]
			B	153-692	[»]
3M0C	X-ray	7.01	A	29-152	[»]
			B	153-692	[»]
3P5B	X-ray	3.30	A	153-692	[»]
			P	61-152	[»]
3P5C	X-ray	4.20	A	153-692	[»]
			P	61-152	[»]
3SQO	X-ray	2.70	A	153-692	[»]
			P	31-152	[»]

ProteinModelPortal

Q8NBP7.

SMR

Q8NBP7. Positions 61-682.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29694N.

STRING

9606.ENSP00000303208.

Protein family/group databases

MEROPS

S08.039.

PTM databases

PhosphoSite

Q8NBP7.

Polymorphism databases

DMDM

38258175.

Proteomic databases

PaxDb

Q8NBP7.

PRIDE

Q8NBP7.

Protocols and materials databases

DNASU

255738.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000302118; ENSP00000303208; ENSG00000169174.

GeneID

255738.

KEGG

hsa:255738.

UCSC

uc001cyf.2. human.

Organism-specific databases

CTD

255738.

GeneCards

GC01P055505.

H-InvDB

HIX0023558.

HGNC

HGNC:20001. PCSK9.

HPA

CAB025575.

MIM

603776. phenotype.
607786. gene+phenotype.

neXtProt

NX_Q8NBP7.

Orphanet

181434. Benign familial hypobetalipoproteinemia.
406. Familial hypercholesterolemia.

PharmGKB

PA38617.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG1404.

HOGENOM

HOG000049267.

HOVERGEN

HBG053530.

InParanoid

Q8NBP7.

KO

K13050.

OMA

HAPGLEC.

OrthoDB

EOG4SXNC0.

PhylomeDB

Q8NBP7.

Gene expression databases

ArrayExpress

Q8NBP7.

Bgee

Q8NBP7.

CleanEx

HS_PCSK9.

Genevestigator

Q8NBP7.

GermOnline

ENSG00000169174. Homo sapiens.

Family and domain databases

Gene3D

3.40.50.200. 1 hit.

InterPro

IPR010259. Inhibitor_I9.
IPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Prot_inh_propept.
[Graphical view]

PANTHER

PTHR10795. PTHR10795. 1 hit.

Pfam

PF05922. Inhibitor_I9. 1 hit.
PF00082. Peptidase_S8. 1 hit.
[Graphical view]

PRINTS

PR00723. SUBTILISIN.

SUPFAM

SSF52743. Pept_S8_S53. 1 hit.
SSF54897. Prot_inh_propept. 1 hit.

PROSITE

PS00136. SUBTILASE_ASP. False negative.
PS00137. SUBTILASE_HIS. False negative.
PS00138. SUBTILASE_SER. False negative.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q8NBP7.

ChEMBL

CHEMBL2929.

EvolutionaryTrace

Q8NBP7.

GenomeRNAi

255738.

NextBio

92626.

SOURCE

Search...

Entry information

Entry name

PCSK9_HUMAN

Accession

Primary (citable) accession number: Q8NBP7
Secondary accession number(s): A8T640 , C0JYY9, Q5PSM5, Q5SZQ2

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 7, 2003
Last sequence update:	January 11, 2011
Last modified:	May 1, 2013
This is version 120 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.