| IED ID | IndEnz0002000797 |
| Enzyme Type ID | protease000797 |
| Protein Name |
Proprotein convertase subtilisin/kexin type 9 EC 3.4.21.- Proprotein convertase 9 PC9 Subtilisin/kexin-like protease PC9 |
| Gene Name | PCSK9 |
| Organism | Macaca mulatta (Rhesus macaque) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Cercopithecoidea Cercopithecidae (Old World monkeys) Cercopithecinae Macaca (macaques) Macaca mulatta (Rhesus macaque) |
| Enzyme Sequence | MGTVSSRRSWWPLPLPLLLLLLLGPAGARAQEDEDGDYEELVLALRSEEDGLADAPEHGATATFHRCAKDPWRLPGTYVVVLKEETHRSQSERTARRLQAQAARRGYLTKILHVFHHLLPGFLVKMSGDLLELALKLPHVDYIEEDSSVFAQSIPWNLERITPARYRADEYQPPKGGSLVEVYLLDTSIQSDHREIEGRVMVTDFESVPEEDGTRFHRQASKCDSHGTHLAGVVSGRDAGVAKGAGLRSLRVLNCQGKGTVSGTLIGLEFIRKSQLVQPVGPLVVLLPLAGGYSRVFNAACQRLARAGVVLVTAAGNFRDDACLYSPASAPEVITVGATNAQDQPVTLGTLGTNFGRCVDLFAPGEDIIGASSDCSTCFVSRSGTSQAAAHVAGIAAMMLSAEPELTLAELRQRLIHFSAKDVINEAWFPEDQRVLTPNLVAALPPSTHRAGWQLFCRTVWSAHSGPTRMATAVARCAQDEELLSCSSFSRSGKRRGERIEAQGGKRVCRAHNAFGGEGVYAIARCCLLPQVNCSVHTAPPAGASMGTRVHCHQQGHVLTGCSSHWEVEDLGTHKPPVLRPRGQPNQCVGHREASIHASCCHAPGLECKVKEHGIPAPQEQVIVACEDGWTLTGCSPLPGTSHVLGAYAVDNTCVVRSRDVSTTGSTSKEAVAAVAICCRSRHLVQASQELQ |
| Enzyme Length | 692 |
| Uniprot Accession Number | A8T666 |
| Absorption | |
| Active Site | ACT_SITE 186; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240; ACT_SITE 226; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240; ACT_SITE 386; /note=Charge relay system; /evidence=ECO:0000255|PROSITE-ProRule:PRU01240 |
| Activity Regulation | ACTIVITY REGULATION: Its proteolytic activity is autoinhibited by the non-covalent binding of the propeptide to the catalytic domain. Inhibited by EGTA (By similarity). {ECO:0000250}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | 3.4.21.- |
| Enzyme 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. 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). {ECO:0000250}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Chain (1); Disulfide bond (11); Domain (2); Glycosylation (1); Modified residue (3); Propeptide (1); Region (1); Signal peptide (1); Site (2) |
| Keywords | Apoptosis;Autocatalytic cleavage;Calcium;Cholesterol metabolism;Cytoplasm;Disulfide bond;Endoplasmic reticulum;Endosome;Glycoprotein;Golgi apparatus;Hydrolase;Lipid metabolism;Lysosome;Phosphoprotein;Protease;Reference proteome;Secreted;Serine protease;Signal;Steroid metabolism;Sterol metabolism;Sulfation;Zymogen |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Secreted {ECO:0000250}. Endosome {ECO:0000250}. Lysosome {ECO:0000250}. Cell surface {ECO:0000250}. Endoplasmic reticulum {ECO:0000250}. Golgi apparatus {ECO:0000250}. 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). {ECO:0000250}. |
| Modified Residue | MOD_RES 38; /note=Sulfotyrosine; /evidence=ECO:0000250; MOD_RES 47; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8NBP7; MOD_RES 688; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8NBP7 |
| Post Translational Modification | PTM: Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. {ECO:0000250}.; 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 (By similarity). {ECO:0000250}.; PTM: Phosphorylation protects the propeptide against proteolysis. {ECO:0000250}. |
| Signal Peptide | SIGNAL 1..30; /evidence=ECO:0000250 |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| Motif | |
| Gene Encoded By | |
| Mass | 74,528 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |