Human Gene PCSK9 (ENST00000302118.5_5) from GENCODE V47lift37
Description: 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:18799458, PubMed:17461796, PubMed:18197702, 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. (from UniProt Q8NBP7) Gencode Transcript: ENST00000302118.5_5 Gencode Gene: ENSG00000169174.13_11 Transcript (Including UTRs) Position: hg19 chr1:55,505,221-55,530,525 Size: 25,305 Total Exon Count: 12 Strand: + Coding Region Position: hg19 chr1:55,505,511-55,529,257 Size: 23,747 Coding Exon Count: 12
ID:PCSK9_HUMAN DESCRIPTION: RecName: Full=Proprotein convertase subtilisin/kexin type 9; EC=3.4.21.-; AltName: Full=Neural apoptosis-regulated convertase 1; Short=NARC-1; AltName: Full=Proprotein convertase 9; Short=PC9; AltName: Full=Subtilisin/kexin-like protease PC9; Flags: Precursor; 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. 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: 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. 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. 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 (PubMed:22027821). DOMAIN: The catalytic domain is responsible for mediating its self-association. PTM: Cleavage by furin and PCSK5 generates a truncated inactive protein that is unable to induce LDLR degradation. 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. PTM: 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. POLYMORPHISM: Genetic variations in PCSK9 define the low density lipoprotein cholesterol level quantitative trait locus 1 (LDLCQ1) [MIM:603776]. DISEASE: Defects in PCSK9 are the cause of hypercholesterolemia autosomal dominant type 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. SIMILARITY: Belongs to the peptidase S8 family. SIMILARITY: Contains 1 peptidase S8 domain. SEQUENCE CAUTION: Sequence=BAC11572.1; Type=Frameshift; Positions=494; WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/pcsk9/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q8NBP7
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0001822 kidney development GO:0001889 liver development GO:0001920 negative regulation of receptor recycling GO:0002092 positive regulation of receptor internalization GO:0006508 proteolysis GO:0006629 lipid metabolic process GO:0006641 triglyceride metabolic process GO:0006644 phospholipid metabolic process GO:0006915 apoptotic process GO:0007041 lysosomal transport GO:0008202 steroid metabolic process GO:0008203 cholesterol metabolic process GO:0009267 cellular response to starvation GO:0010469 regulation of receptor activity GO:0010989 negative regulation of low-density lipoprotein particle clearance GO:0016485 protein processing GO:0016540 protein autoprocessing GO:0022008 neurogenesis GO:0030182 neuron differentiation GO:0032799 low-density lipoprotein receptor particle metabolic process GO:0032802 low-density lipoprotein particle receptor catabolic process GO:0032803 regulation of low-density lipoprotein particle receptor catabolic process GO:0032805 positive regulation of low-density lipoprotein particle receptor catabolic process GO:0032869 cellular response to insulin stimulus GO:0034383 low-density lipoprotein particle clearance GO:0042157 lipoprotein metabolic process GO:0042632 cholesterol homeostasis GO:0043523 regulation of neuron apoptotic process GO:0043525 positive regulation of neuron apoptotic process GO:0043687 post-translational protein modification GO:0044267 cellular protein metabolic process GO:1905596 negative regulation of low-density lipoprotein particle receptor binding GO:1905598 negative regulation of low-density lipoprotein receptor activity GO:1905601 negative regulation of receptor-mediated endocytosis involved in cholesterol transport GO:2000272 negative regulation of receptor activity GO:2000650 negative regulation of sodium ion transmembrane transporter activity
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Common Gene Haplotype Alleles 
