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Protein

Proprotein convertase subtilisin/kexin type 9

Gene

Pcsk9

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Crucial player in the regulation of plasma cholesterol homeostasis. Binds to low-density lipid receptor family members: low density lipoprotein receptor (LDLR), very low density lipoprotein receptor (VLDLR), apolipoprotein E receptor (LRP1/APOER) and apolipoprotein receptor 2 (LRP8/APOER2), and promotes their degradation in intracellular acidic compartments. 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 (By similarity).By similarity

Cofactori

Ca2+By similarity

Enzyme regulationi

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

pH dependencei

Optimum pH is 8-11.

Temperature dependencei

Optimum temperature is 37 degrees Celsius.

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei185 – 1851Charge relay systemBy similarity
Active sitei225 – 2251Charge relay systemBy similarity
Active sitei385 – 3851Charge relay systemBy similarity

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Protease, Serine protease

Keywords - Biological processi

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

Keywords - Ligandi

Calcium

Protein family/group databases

MEROPSiS08.039.

Names & Taxonomyi

Protein namesi
Recommended name:
Proprotein convertase subtilisin/kexin type 9 (EC:3.4.21.-)
Alternative name(s):
Neural apoptosis-regulated convertase 1
Short name:
NARC-1
Proprotein convertase 9
Short name:
PC9
Subtilisin/kexin-like protease PC9
Gene namesi
Name:Pcsk9
Synonyms:Narc1
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 5

Organism-specific databases

RGDi728909. Pcsk9.

Subcellular locationi

  • Cytoplasm By similarity
  • Secreted By similarity
  • 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 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 (By similarity).By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

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

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi151 – 1511Q → E or N: No effect; when associated with A-152. 1 Publication
Mutagenesisi151 – 1511Q → I: Abolishes autocleavage; when associated with V-152. 1 Publication
Mutagenesisi152 – 1521S → A: No effect; when associated with E-151 or N-151. 1 Publication
Mutagenesisi152 – 1521S → V: Abolishes autocleavage; when associated with I-151. 1 Publication
Mutagenesisi225 – 2251H → W: Abolishes autocleavage. 1 Publication
Mutagenesisi385 – 3851S → A: Abolishes autocleavage. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 3030Sequence analysisAdd
BLAST
Propeptidei31 – 151121PRO_0000027124Add
BLAST
Chaini152 – 691540Proprotein convertase subtilisin/kexin type 9PRO_0000027125Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei37 – 371SulfotyrosineBy similarity
Modified residuei46 – 461PhosphoserineBy similarity
Disulfide bondi222 ↔ 254Sequence analysis
Disulfide bondi322 ↔ 357Sequence analysis
Disulfide bondi456 ↔ 526Sequence analysis
Disulfide bondi476 ↔ 525Sequence analysis
Disulfide bondi485 ↔ 508Sequence analysis
Glycosylationi532 – 5321N-linked (GlcNAc...)By similarity
Disulfide bondi533 ↔ 600Sequence analysis
Disulfide bondi551 ↔ 599Sequence analysis
Disulfide bondi561 ↔ 587Sequence analysis
Disulfide bondi607 ↔ 678Sequence analysis
Disulfide bondi625 ↔ 677Sequence analysis
Disulfide bondi634 ↔ 653Sequence analysis
Modified residuei687 – 6871PhosphoserineBy similarity

Post-translational modificationi

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).By similarity
Phosphorylation protects the propeptide against proteolysis.By similarity

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sitei151 – 1522Cleavage; by autolysis
Sitei217 – 2182Cleavage; by furin and PCSK5By similarity

Keywords - PTMi

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

Proteomic databases

PaxDbiP59996.
PRIDEiP59996.

PTM databases

iPTMnetiP59996.
PhosphoSiteiP59996.

Expressioni

Tissue specificityi

Highly expressed in 12-day embryo. In the adult, strongly expressed in liver, small intestine, jejunum, and to a lesser extent in kidney, lung, spleen and thymus. Expression in the liver is up-regulated following partial hepatectomy.

Gene expression databases

BgeeiENSRNOG00000006280.
GenevisibleiP59996. RN.

Interactioni

Subunit structurei

Monomer. Can self-associate to form dimers and higher multimers which may have increased LDLR degrading activity. The precursor protein but not the mature protein may form multimers. Interacts with APOB, VLDLR, LRP8/APOER2 and BACE1. The full length immature form (pro-PCSK9) interacts with SCNN1A, SCNN1B and SCNN1G. The pro-PCSK9 form (via C-terminal domain) interacts with LDLR. Interacts (via the C-terminal domain) with ANXA2 (via repeat Annexin 1); the interaction inhibits the degradation of LDLR.By similarity

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008536.

Structurei

3D structure databases

ProteinModelPortaliP59996.
SMRiP59996. Positions 60-681.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini181 – 422242Peptidase S8Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni449 – 691243C-terminal domainBy similarityAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi495 – 4973Cell attachment siteSequence analysis

Domaini

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

Sequence similaritiesi

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

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG1153. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00490000043472.
HOGENOMiHOG000049267.
HOVERGENiHBG053530.
InParanoidiP59996.
KOiK13050.
OMAiCHAPGLE.
OrthoDBiEOG091G067E.
PhylomeDBiP59996.
TreeFamiTF106271.

Family and domain databases

Gene3Di3.30.70.80. 1 hit.
3.40.50.200. 1 hit.
InterProiIPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Propept_inh.
IPR010259. S8pro/Inhibitor_I9.
[Graphical view]
PANTHERiPTHR10795. PTHR10795. 1 hit.
PfamiPF00082. Peptidase_S8. 1 hit.
[Graphical view]
PRINTSiPR00723. SUBTILISIN.
SUPFAMiSSF52743. SSF52743. 1 hit.
SSF54897. SSF54897. 1 hit.

Sequencei

Sequence statusi: Complete.

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

P59996-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGIRCSTWLR WPLSPQLLLL LLLCPTGSRA QDEDGDYEEL MLALPSQEDS
60 70 80 90 100
LVDEASHVAT ATFRRCSKEA WRLPGTYVVV LMEETQRLQV EQTAHRLQTW
110 120 130 140 150
AARRGYVIKV LHVFYDLFPG FLVKMSSDLL GLALKLPHVE YIEEDSLVFA
160 170 180 190 200
QSIPWNLERI IPAWQQTEED SSPDGSSQVE VYLLDTSIQS GHREIEGRVT
210 220 230 240 250
ITDFNSVPEE DGTRFHRQAS KCDSHGTHLA GVVSGRDAGV AKGTSLHSLR
260 270 280 290 300
VLNCQGKGTV SGTLIGLEFI RKSQLIQPSG PLVVLLPLAG GYSRILNTAC
310 320 330 340 350
QRLARTGVVL VAAAGNFRDD ACLYSPASAP EVITVGATNA QDQPVTLGTL
360 370 380 390 400
GTNFGRCVDL FAPGKDIIGA SSDCSTCYMS QSGTSQAAAH VAGIVAMMLN
410 420 430 440 450
RDPALTLAEL RQRLILFSTK DVINMAWFPE DQRVLTPNRV ATLPPSTQET
460 470 480 490 500
GGQLLCRTVW SAHSGPTRTA TATARCAPEE ELLSCSSFSR SGRRRGDRIE
510 520 530 540 550
AIGGQQVCKA LNAFGGEGVY AVARCCLLPR VNCSIHNTPA ARAGPQTPVH
560 570 580 590 600
CHQKDHVLTG CSFHWEVENL RAQQQPLLRS RHQPGQCVGH QEASVHASCC
610 620 630 640 650
HAPGLECKIK EHGIAGPAEQ VTVACEAGWT LTGCNVLPGA SLPLGAYSVD
660 670 680 690
NVCVARIRDA GRADRTSEEA TVAAAICCRS RPSAKASWVH Q
Length:691
Mass (Da):74,709
Last modified:November 7, 2003 - v1
Checksum:i8084A880CCAE5BA6
GO

Sequence cautioni

The sequence CAC60363 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX207690 Unassigned DNA. Translation: CAC60363.1. Different initiation.
AY847775 mRNA. Translation: AAW31850.1.
BC133063 mRNA. Translation: AAI33064.1.
RefSeqiNP_954862.2. NM_199253.2.
UniGeneiRn.19195.

Genome annotation databases

EnsembliENSRNOT00000008535; ENSRNOP00000008536; ENSRNOG00000006280.
GeneIDi298296.
KEGGirno:298296.
UCSCiRGD:728909. rat.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AX207690 Unassigned DNA. Translation: CAC60363.1. Different initiation.
AY847775 mRNA. Translation: AAW31850.1.
BC133063 mRNA. Translation: AAI33064.1.
RefSeqiNP_954862.2. NM_199253.2.
UniGeneiRn.19195.

3D structure databases

ProteinModelPortaliP59996.
SMRiP59996. Positions 60-681.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10116.ENSRNOP00000008536.

Protein family/group databases

MEROPSiS08.039.

PTM databases

iPTMnetiP59996.
PhosphoSiteiP59996.

Proteomic databases

PaxDbiP59996.
PRIDEiP59996.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000008535; ENSRNOP00000008536; ENSRNOG00000006280.
GeneIDi298296.
KEGGirno:298296.
UCSCiRGD:728909. rat.

Organism-specific databases

CTDi255738.
RGDi728909. Pcsk9.

Phylogenomic databases

eggNOGiKOG1153. Eukaryota.
COG1404. LUCA.
GeneTreeiENSGT00490000043472.
HOGENOMiHOG000049267.
HOVERGENiHBG053530.
InParanoidiP59996.
KOiK13050.
OMAiCHAPGLE.
OrthoDBiEOG091G067E.
PhylomeDBiP59996.
TreeFamiTF106271.

Miscellaneous databases

PROiP59996.

Gene expression databases

BgeeiENSRNOG00000006280.
GenevisibleiP59996. RN.

Family and domain databases

Gene3Di3.30.70.80. 1 hit.
3.40.50.200. 1 hit.
InterProiIPR000209. Peptidase_S8/S53_dom.
IPR015500. Peptidase_S8_subtilisin-rel.
IPR009020. Propept_inh.
IPR010259. S8pro/Inhibitor_I9.
[Graphical view]
PANTHERiPTHR10795. PTHR10795. 1 hit.
PfamiPF00082. Peptidase_S8. 1 hit.
[Graphical view]
PRINTSiPR00723. SUBTILISIN.
SUPFAMiSSF52743. SSF52743. 1 hit.
SSF54897. SSF54897. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiPCSK9_RAT
AccessioniPrimary (citable) accession number: P59996
Secondary accession number(s): Q5I6U6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: November 7, 2003
Last sequence update: November 7, 2003
Last modified: September 7, 2016
This is version 110 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Peptidase families
    Classification of peptidase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

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