PCSK9
entrez
255738
canonical
uniprot
Q8NBP7
canonical
ensembl
ENSG00000169174
resolver
ensp
ENSP00000303208
resolver
ensp
ENSP00000501257
resolver
ensp
ENSP00000519088
resolver
ensp
ENSP00000525042
resolver
ensp
ENSP00000593635
resolver
enst
ENST00000673903
resolver
enst
ENST00000713786
resolver
genesymbol
PCSK9
resolver
genesymbol_syn
NARC1
resolver
hgnc
HGNC:20001
resolver
uniprot
A0A669KBG0
resolver
uniprot
A0AAQ5BGX4
resolver
uniprot
A8T640
resolver
uniprot
C0JYY9
resolver
uniprot
Q5PSM5
resolver
uniprot
Q5SZQ2
resolver
uniprot_entry
A0A669KBG0_HUMAN
resolver
uniprot_entry
A0AAQ5BGX4_HUMAN
resolver
uniprot_entry
PCSK9_HUMAN
resolver
uniprot_sec
A8T640
resolver
uniprot_sec
C0JYY9
resolver
uniprot_sec
Q5PSM5
resolver
uniprot_sec
Q5SZQ2
resolver
activity_regulation
ACTIVITY REGULATION: Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA.
uniprot
proteins
amino_acid_sequence
MGTVSSRRSWWPLPLLLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLAEAPEHGTTATFHRCAKDPWRLPGTYVVVLKEETHLSQSERTARRLQAQAARRGYLTKILHVFHGLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPPRYRADEYQPPDGGSLVEVYLLDTSIQSDHREIEGRVMVTDFENVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGASMRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVLNAACQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVDLFAPGEDIIGASSDCSTCFVSQSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPEDQRVLTPNLVAALPPSTHGAGWQLFCRTVWSAHSGPTRMATAVARCAPDEELLSCSSFSRSGKRRGERMEAQGGKLVCRAHNAFGGEGVYAIARCCLLPQANCSVHTAPPAEASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVTVACEEGWTLTGCSALPGTSHVLGAYAVDNTCVVRSRDVSTTGSTSEGAVTAVAICCRSRHLAQASQELQ
uniprot
proteins
disease_involvement
DISEASE: Hypercholesterolemia, familial, 3 (FHCL3) [MIM:603776]: A form of hypercholesterolemia, a disorder of lipoprotein metabolism characterized by elevated serum low-density lipoprotein (LDL) cholesterol levels, which result in excess deposition of cholesterol in tissues and leads to xanthelasma, xanthomas, accelerated atherosclerosis and increased risk of premature coronary heart disease. FHCL3 inheritance is autosomal dominant. {ECO:0000269|PubMed:12730697, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:19191301, ECO:0000269|PubMed:22095935, ECO:0000269|PubMed:24808179}. Note=The disease is caused by variants affecting the gene represented in this entry.
uniprot
proteins
ec_number
3.4.21.-
uniprot
proteins
function
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 (PubMed:18039658). Acts via a non-proteolytic mechanism to enhance the degradation of the hepatic LDLR through a clathrin LDLRAP1/ARH-mediated pathway. May prevent the recycling of LDLR from endosomes to the cell surface or direct it to lysosomes for degradation. Can induce ubiquitination of LDLR leading to its subsequent degradation (PubMed:17461796, PubMed:18197702, PubMed:18799458, PubMed:22074827). Inhibits intracellular degradation of APOB via the autophagosome/lysosome pathway in a LDLR-independent manner. Involved in the disposal of non-acetylated intermediates of BACE1 in the early secretory pathway (PubMed:18660751). Inhibits epithelial Na(+) channel (ENaC)-mediated Na(+) absorption by reducing ENaC surface expression primarily by increasing its proteasomal degradation. Regulates neuronal apoptosis via modulation of LRP8/APOER2 levels and related anti-apoptotic signaling pathways. {ECO:0000269|PubMed:17461796, ECO:0000269|PubMed:18039658, ECO:0000269|PubMed:18197702, ECO:0000269|PubMed:18660751, ECO:0000269|PubMed:18799458, ECO:0000269|PubMed:22074827, ECO:0000269|PubMed:22493497, ECO:0000269|PubMed:22580899}.
uniprot
proteins
mass_dalton
74286
uniprot
proteins
mutagenesis
MUTAGEN 67; /note="C->A: Does not affect multimerization or zymogen processing."; /evidence="ECO:0000269|PubMed:12552133"; MUTAGEN 226; /note="H->A: Remains in the endoplasmic reticulum and is not secreted."; /evidence="ECO:0000269|PubMed:12552133"; MUTAGEN 533; /note="N->A: 1.5 kDa decrease of the apparent molecular mass of pro-PCSK9 and PCSK9 and no effect on processing and secretion."; /evidence="ECO:0000269|PubMed:12552133
uniprot
proteins
post_translational_modification
PTM: Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. {ECO:0000269|PubMed:16912035}.; PTM: 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. {ECO:0000269|PubMed:14622975}.; PTM: Phosphorylation protects the propeptide against proteolysis. {ECO:0000269|PubMed:18498363}.
uniprot
proteins
protein_family
Peptidase S8 family
uniprot
proteins
pubmed
12552133
uniprot
proteins
pubmed
12730697
uniprot
proteins
pubmed
14622975
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
16465619
uniprot
proteins
pubmed
16710414
uniprot
proteins
pubmed
16912035
uniprot
proteins
pubmed
17081983
uniprot
proteins
pubmed
17461796
uniprot
proteins
pubmed
17502100
uniprot
proteins
pubmed
17971861
uniprot
proteins
pubmed
18039658
uniprot
proteins
pubmed
18197702
uniprot
proteins
pubmed
18280815
uniprot
proteins
pubmed
18498363
uniprot
proteins
pubmed
18649882
uniprot
proteins
pubmed
18660751
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18799458
uniprot
proteins
pubmed
19020338
uniprot
proteins
pubmed
19191301
uniprot
proteins
pubmed
19319977
uniprot
proteins
pubmed
19930098
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
21149300
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
21943799
uniprot
proteins
pubmed
22027821
uniprot
proteins
pubmed
22074827
uniprot
proteins
pubmed
22095935
uniprot
proteins
pubmed
22417841
uniprot
proteins
pubmed
22493497
uniprot
proteins
pubmed
22580899
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
24808179
uniprot
proteins
pubmed
26091039
uniprot
proteins
sequence_length
692
uniprot
proteins
subcellular_location
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.
uniprot
proteins