Q80W65 (PCSK9_MOUSE) 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

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	694 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.9 Ref.10
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 By similarity.
Subcellular location	Cytoplasm By similarity. Secreted. Endosome By similarity. Lysosome By similarity. Cell surface By similarity. Endoplasmic reticulum By similarity. Golgi apparatus By similarity. 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 By similarity.
Tissue specificity	Hepatocytes, kidney mesenchymal cells, intestinal ileum, colon epithelia and embryonic brain telencephalon neurons.
Developmental stage	In the embryo, expressed in the liver at day E9, in the skin and transiently in the telencephalon at day E12, and in the kidney, small intestine and cerebellum at E15.
Induction	Down-regulated following a high-cholesterol diet. Ref.2
Domain	The C-terminal domain (CRD) is essential for the LDLR-binding and degrading activities By similarity. The catalytic domain is responsible for mediating its self-association By similarity.
Post-translational modification	Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation By similarity. 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 By similarity. Ref.6 Ref.7 Phosphorylation protects the propeptide against proteolysis By similarity.
Sequence similarities	Belongs to the peptidase S8 family. Contains 1 peptidase S8 domain.
Sequence caution	The sequence AAP31672.1 differs from that shown. Reason: Erroneous initiation. The sequence BAE28934.1 differs from that shown. Reason: Erroneous initiation. The sequence CAC60362.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Apoptosis Cholesterol metabolism Lipid metabolism Steroid metabolism Sterol metabolism
Cellular component	Cytoplasm Endoplasmic reticulum Endosome Golgi apparatus Lysosome Secreted
Domain	Signal
Ligand	Calcium
Molecular function	Hydrolase Protease Serine protease
PTM	Autocatalytic cleavage Disulfide bond Glycoprotein Phosphoprotein Sulfation Zymogen
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW cellular response to insulin stimulus Inferred from direct assay PubMed 16407292. Source: HGNC cellular response to starvation Inferred from direct assay PubMed 16407292. Source: HGNC cholesterol homeostasis Inferred from sequence or structural similarity Ref.6. Source: HGNC cholesterol metabolic process Inferred from direct assay PubMed 17242417. Source: MGI induction of apoptosis Inferred from electronic annotation. Source: Compara kidney development Inferred from expression pattern Ref.6. Source: HGNC lipoprotein metabolic process Inferred from direct assay PubMed 17242417. Source: MGI liver development Inferred from expression pattern Ref.6. Source: HGNC low-density lipoprotein particle receptor catabolic process Inferred from sequence or structural similarity. Source: UniProtKB lysosomal transport Inferred from electronic annotation. Source: Compara negative regulation of catalytic activity Inferred from electronic annotation. Source: InterPro negative regulation of low-density lipoprotein particle clearance Inferred from electronic annotation. Source: Compara negative regulation of receptor recycling Inferred from electronic annotation. Source: Compara neuron differentiation Inferred from direct assay PubMed 16893422. Source: HGNC phospholipid metabolic process Inferred from direct assay PubMed 17242417. Source: MGI positive regulation of neuron apoptotic process Inferred from sequence or structural similarity Ref.6. Source: HGNC positive regulation of receptor internalization Inferred from electronic annotation. Source: Compara protein autoprocessing Inferred from sequence or structural similarity Ref.6. Source: HGNC proteolysis Inferred from Biological aspect of Ancestor. Source: RefGenome regulation of low-density lipoprotein particle receptor catabolic process Inferred from mutant phenotype PubMed 15741654PubMed 15805190. Source: MGI regulation of receptor activity Inferred from electronic annotation. Source: Compara triglyceride metabolic process Inferred from direct assay PubMed 17242417. Source: MGI
Cellular_component	Golgi apparatus Inferred from sequence or structural similarity. Source: UniProtKB cell surface Inferred from sequence or structural similarity. Source: UniProtKB early endosome Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum lumen Traceable author statement. Source: Reactome extracellular space Inferred from direct assay PubMed 17080197. Source: HGNC late endosome Inferred from sequence or structural similarity. Source: UniProtKB lysosome Inferred from sequence or structural similarity. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara rough endoplasmic reticulum Inferred from electronic annotation. Source: Compara
Molecular_function	apolipoprotein binding Inferred from direct assay Ref.9. Source: UniProtKB low-density lipoprotein particle binding Inferred from direct assay Ref.9. Source: UniProtKB low-density lipoprotein particle receptor binding Inferred from direct assay PubMed 17080197. Source: HGNC protein self-association Inferred from sequence or structural similarity. Source: UniProtKB serine-type endopeptidase activity Inferred from sequence or structural similarity Ref.6. Source: HGNC sodium channel inhibitor activity Inferred from electronic annotation. Source: Compara very-low-density lipoprotein particle binding Inferred from direct assay Ref.9. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 34	34	Potential
	Propeptide	35 – 155	121			PRO_0000027122
	Chain	156 – 694	539	Proprotein convertase subtilisin/kexin type 9		PRO_0000027123
Regions
	Domain	166 – 432	267	Peptidase S8
	Region	156 – 452	297	Catalytic domain By similarity
	Region	453 – 694	242	C-terminal domain By similarity
	Motif	499 – 501	3	Cell attachment site Potential
Sites
	Active site	189	1	Charge relay system By similarity
	Active site	229	1	Charge relay system By similarity
	Active site	389	1	Charge relay system By similarity
	Site	155 – 156	2	Cleavage; by autolysis By similarity
	Site	221 – 222	2	Cleavage; by furin and PCSK5 By similarity
Amino acid modifications
	Modified residue	41	1	Sulfotyrosine By similarity
	Modified residue	50	1	Phosphoserine Ref.8
	Modified residue	691	1	Phosphoserine By similarity
	Glycosylation	536	1	N-linked (GlcNAc...) By similarity
	Disulfide bond	226 ↔ 258		Potential
	Disulfide bond	326 ↔ 361		Potential
	Disulfide bond	460 ↔ 530		Potential
	Disulfide bond	480 ↔ 529		Potential
	Disulfide bond	489 ↔ 512		Potential
	Disulfide bond	537 ↔ 604		Potential
	Disulfide bond	555 ↔ 603		Potential
	Disulfide bond	565 ↔ 591		Potential
	Disulfide bond	611 ↔ 682		Potential
	Disulfide bond	629 ↔ 681		Potential
	Disulfide bond	638 ↔ 657		Potential
Experimental info
	Sequence conflict	17 – 19	3	Missing in CAC60362. Ref.1
	Sequence conflict	34	1	A → T in CAC60362. Ref.1
	Sequence conflict	189	1	D → G in CAC60362. Ref.1
	Sequence conflict	196	1	H → Y in CAC60362. Ref.1
	Sequence conflict	200	1	E → A in CAC60362. Ref.1
	Sequence conflict	305	1	R → Q in CAC60362. Ref.1
	Sequence conflict	534	1	R → H in CAC60362. Ref.1
	Sequence conflict	626	1	T → A in CAC60362. Ref.1

Sequences

	Sequence		Length	Mass (Da)
	Q80W65 [UniParc]. Last modified November 7, 2003. Version 2. Checksum: 977BD4BD1FAF98C0	FASTA	694	74,823
	10 20 30 40 50 60 MGTHCSAWLR WPLLPLLPPL LLLLLLLCPT GAGAQDEDGD YEELMLALPS QEDGLADEAA 70 80 90 100 110 120 HVATATFRRC SKEAWRLPGT YIVVLMEETQ RLQIEQTAHR LQTRAARRGY VIKVLHIFYD 130 140 150 160 170 180 LFPGFLVKMS SDLLGLALKL PHVEYIEEDS FVFAQSIPWN LERIIPAWHQ TEEDRSPDGS 190 200 210 220 230 240 SQVEVYLLDT SIQGAHREIE GRVTITDFNS VPEEDGTRFH RQASKCDSHG THLAGVVSGR 250 260 270 280 290 300 DAGVAKGTSL HSLRVLNCQG KGTVSGTLIG LEFIRKSQLI QPSGPLVVLL PLAGGYSRIL 310 320 330 340 350 360 NAACRHLART GVVLVAAAGN FRDDACLYSP ASAPEVITVG ATNAQDQPVT LGTLGTNFGR 370 380 390 400 410 420 CVDLFAPGKD IIGASSDCST CFMSQSGTSQ AAAHVAGIVA RMLSREPTLT LAELRQRLIH 430 440 450 460 470 480 FSTKDVINMA WFPEDQQVLT PNLVATLPPS THETGGQLLC RTVWSAHSGP TRTATATARC 490 500 510 520 530 540 APEEELLSCS SFSRSGRRRG DWIEAIGGQQ VCKALNAFGG EGVYAVARCC LVPRANCSIH 550 560 570 580 590 600 NTPAARAGLE THVHCHQKDH VLTGCSFHWE VEDLSVRRQP ALRSRRQPGQ CVGHQAASVY 610 620 630 640 650 660 ASCCHAPGLE CKIKEHGISG PSEQVTVACE AGWTLTGCNV LPGASLTLGA YSVDNLCVAR 670 680 690 VHDTARADRT SGEATVAAAI CCRSRPSAKA SWVQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Narc-1, novel subtilase-like homologs." Chiang L.W. Patent number WO0157081, 09-AUG-2001 Cited for: NUCLEOTIDE SEQUENCE.
[2]	"Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice." Maxwell K.N., Soccio R.E., Duncan E.M., Sehayek E., Breslow J.L. J. Lipid Res. 44:2109-2119(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INDUCTION. Strain: C57BL/6. Tissue: Liver.
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Liver.
[4]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. Strain: C57BL/6J.
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6. Tissue: Eye.
[6]	"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: IDENTIFICATION OF PROPEPTIDE CLEAVAGE SITE, CHARACTERIZATION.
[7]	"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.
[8]	"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-50, MASS SPECTROMETRY.
[9]	"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.
[10]	"PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling." Kysenius K., Muggalla P., Maetlik K., Arumaee U., Huttunen H.J. Cell. Mol. Life Sci. 69:1903-1916(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AX207688 Unassigned DNA. Translation: CAC60362.1. Different initiation. AY273821 mRNA. Translation: AAP31672.1. Different initiation. AK149520 mRNA. Translation: BAE28934.1. Different initiation. AL954352 Genomic DNA. Translation: CAM15751.1. BC038085 mRNA. Translation: AAH38085.1.
IPI	IPI00377933.
RefSeq	NP_705793.1. NM_153565.2.
UniGene	Mm.133268.
3D structure databases
ProteinModelPortal	Q80W65.
SMR	Q80W65. Positions 64-685.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000055757.
Protein family/group databases
MEROPS	S08.039.
PTM databases
PhosphoSite	Q80W65.
Proteomic databases
PaxDb	Q80W65.
PRIDE	Q80W65.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000049507; ENSMUSP00000055757; ENSMUSG00000044254.
GeneID	100102.
KEGG	mmu:100102.
UCSC	uc008tyi.2. mouse.
Organism-specific databases
CTD	255738.
MGI	MGI:2140260. Pcsk9.
Phylogenomic databases
eggNOG	COG1404.
GeneTree	ENSGT00490000043472.
HOGENOM	HOG000049267.
HOVERGEN	HBG053530.
InParanoid	B1AZI4.
KO	K13050.
OMA	HAPGLEC.
OrthoDB	EOG4SXNC0.
Enzyme and pathway databases
Reactome	REACT_115202. Signal Transduction.
Gene expression databases
Bgee	Q80W65.
CleanEx	MM_PCSK9.
Genevestigator	Q80W65.
GermOnline	ENSMUSG00000044254. Mus musculus.
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
NextBio	354261.
SOURCE	Search...

Entry information

Entry name

PCSK9_MOUSE

Accession

Primary (citable) accession number: Q80W65
Secondary accession number(s): B1AZI4 , Q3UEH7, Q8BXW9, Q8CFT6

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 7, 2003
Last sequence update:	November 7, 2003
Last modified:	May 1, 2013
This is version 99 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program