Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatocyte-secreted proteinase K-like subtilase that regulates plasma LDL cholesterol by controlling the number of LDL receptors on the liver surface. Pro-PCSK9 cleaves its own prodomain in the endoplasmic reticulum; the prodomain stays bound as an inhibitor, so the secreted enzyme has no known trans substrate. Circulating PCSK9 binds the EGF-A repeat of LDLR at the cell surface, is internalized with it, and binds more tightly at endosomal pH, which prevents the conformational change needed for receptor recycling and diverts LDLR to lysosomes for degradation. This activity does not require catalysis. PCSK9 similarly targets VLDLR and ApoER2. Its expression is driven by SREBP-2 and insulin/SREBP-1c and inhibited by fasting; annexin A2 is an endogenous inhibitor. Gain-of-function variants cause autosomal dominant hypercholesterolemia, while loss-of-function variants lower LDL cholesterol and coronary risk, making PCSK9 a therapeutic target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001822 kidney development | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0001822 kidney development | ISS PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0001889 liver development | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0001889 liver development | ISS PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0001920 negative regulation of receptor recycling | IDA PMID:17452316 Binding of proprotein convertase subtilisin/kexin type 9 to ... | ACCEPT | Summary: PCSK9 blocks LDLR recycling. Reason: PCSK9 binding to EGF-A prevents the acid-dependent conformational change required for LDLR recycling. Supporting Evidence: PMID:17452316 These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. PMID:22081141 Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. |
| GO:0001920 negative regulation of receptor recycling | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | ACCEPT | Summary: PCSK9 blocks LDLR recycling. Reason: PCSK9 binding to EGF-A prevents the acid-dependent conformational change required for LDLR recycling. Supporting Evidence: PMID:17452316 These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. PMID:22081141 Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. |
| GO:0002091 negative regulation of receptor internalization | IDA PMID:18799458 Annexin A2 is a C-terminal PCSK9-binding protein that regula... | UNDECIDED | Summary: Negative regulation of receptor internalization; could not be verified. Reason: The cited annexin A2 study is abstract-only in the cache; the abstract reports PCSK9-AnxA2 binding and co-localization, not an effect of PCSK9 on receptor internalization. The curator's full-text basis could not be checked. Supporting Evidence: PMID:18799458 Immunocytochemistry revealed that PCSK9 and AnxA2 co-localize at the cell surface, indicating a possible competition with the LDLR. |
| GO:0002092 positive regulation of receptor internalization | IDA PMID:17328821 Degradation of the LDL receptors by PCSK9 is not mediated by... | MARK AS OVER ANNOTATED | Summary: Not supported: PCSK9 reduces LDL internalization. Reason: The cited study shows PCSK9-containing medium reduces LDL internalization by HepG2 cells and that degradation requires an intracellular acidic compartment. PCSK9 is internalized with LDLR, but the study does not show that PCSK9 increases the rate of receptor internalization. Supporting Evidence: PMID:17328821 The ability of the conditioned medium to reduce the internalization of LDL was abolished by removal of recombinant PCSK9 from the conditioned medium by affinity chromatography. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | MARK AS OVER ANNOTATED | Summary: RNA binding from a high-throughput HeLa interactome screen. Reason: PCSK9 is a secreted protein; detection in a HeLa mRNA-interactome capture screen does not establish a functional RNA-binding role. |
| GO:0004175 endopeptidase activity | IDA PMID:16912035 The proprotein convertase (PC) PCSK9 is inactivated by furin... | ACCEPT | Summary: Endopeptidase activity (autocatalytic). Reason: Correct parent of serine-type endopeptidase activity; the activity is self-directed. Supporting Evidence: PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase |
| GO:0004252 serine-type endopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Serine endopeptidase activity is genuine but used only for autocatalytic prodomain cleavage. Reason: PCSK9 is a proteinase K-like subtilase that cleaves its own prodomain intramolecularly in the ER, a step required for its secretion. No trans substrate is known, and LDLR degradation does not require catalytic activity, so this activity supports maturation rather than LDL regulation. Supporting Evidence: PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0004252 serine-type endopeptidase activity | IDA PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | ACCEPT | Summary: Serine endopeptidase activity is genuine but used only for autocatalytic prodomain cleavage. Reason: PCSK9 is a proteinase K-like subtilase that cleaves its own prodomain intramolecularly in the ER, a step required for its secretion. No trans substrate is known, and LDLR degradation does not require catalytic activity, so this activity supports maturation rather than LDL regulation. Supporting Evidence: PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0004252 serine-type endopeptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Serine endopeptidase activity is genuine but used only for autocatalytic prodomain cleavage. Reason: PCSK9 is a proteinase K-like subtilase that cleaves its own prodomain intramolecularly in the ER, a step required for its secretion. No trans substrate is known, and LDLR degradation does not require catalytic activity, so this activity supports maturation rather than LDL regulation. Supporting Evidence: PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0005515 protein binding | IPI PMID:17461796 The cellular trafficking of the secretory proprotein convert... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:18799458 Annexin A2 is a C-terminal PCSK9-binding protein that regula... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22081141 Mechanistic implications for LDL receptor degradation from t... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22493497 Regulation of epithelial sodium channel trafficking by propr... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22493497 Regulation of epithelial sodium channel trafficking by propr... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22493497 Regulation of epithelial sodium channel trafficking by propr... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22580899 Proprotein convertase subtilisin/kexin type 9 interacts with... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:25613181 MMP-2 inhibits PCSK9-induced degradation of the LDL receptor... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005515 protein binding | IPI PMID:25613181 MMP-2 inhibits PCSK9-induced degradation of the LDL receptor... | REMOVE | Summary: Uninformative protein binding; specific partners are captured by more specific terms. Reason: The IPI evidence reports physical interactions (LDLR, annexin A2, ENaC subunits, apoB, MMP-2), but 'protein binding' conveys no function. The functionally important interaction, binding the LDLR EGF-A repeat, is captured by GO:0050750 and the PCSK9-LDLR complex. Removal does not mean the reported interactions are false. |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | IDA PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | IDA PMID:16912035 The proprotein convertase (PC) PCSK9 is inactivated by furin... | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | IDA PMID:17080197 Secreted PCSK9 decreases the number of LDL receptors in hepa... | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6784729 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6784734 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6784735 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855111 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855130 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8855131 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9733403 | ACCEPT | Summary: PCSK9 is secreted into plasma. Reason: Mature PCSK9 (with its prodomain bound) is secreted by hepatocytes and acts on LDLR from the circulation. Supporting Evidence: PMID:16912035 Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. |
| GO:0005737 cytoplasm | IDA PMID:22580899 Proprotein convertase subtilisin/kexin type 9 interacts with... | KEEP AS NON CORE | Summary: Cytoplasm is imprecise for a secretory protein. Reason: PCSK9 resides in the secretory and endocytic lumen; 'cytoplasm' (in the GO sense, including organelles) is correct but uninformative. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasm is imprecise for a secretory protein. Reason: PCSK9 resides in the secretory and endocytic lumen; 'cytoplasm' (in the GO sense, including organelles) is correct but uninformative. |
| GO:0005764 lysosome | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | KEEP AS NON CORE | Summary: Lysosome; PCSK9 is degraded with LDLR. Reason: PCSK9 accompanies LDLR to lysosomes where the complex is degraded; a fate rather than a site of activity. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0005764 lysosome | IDA PMID:18039658 The proprotein convertase PCSK9 induces the degradation of l... | KEEP AS NON CORE | Summary: Lysosome; PCSK9 is degraded with LDLR. Reason: PCSK9 accompanies LDLR to lysosomes where the complex is degraded; a fate rather than a site of activity. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0005764 lysosome | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Lysosome; PCSK9 is degraded with LDLR. Reason: PCSK9 accompanies LDLR to lysosomes where the complex is degraded; a fate rather than a site of activity. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0005765 lysosomal membrane | TAS Reactome:R-HSA-8855130 | KEEP AS NON CORE | Summary: Lysosomal membrane association with LDLR. Reason: PCSK9 is luminal/bound to the LDLR ectodomain; lysosomal membrane localization reflects co-delivery with the receptor. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0005768 endosome | IEA GO_REF:0000044 | ACCEPT | Summary: Endosomal localization with LDLR. Reason: PCSK9 is co-internalized with LDLR into endosomes, where tighter acid-pH binding prevents receptor recycling. Supporting Evidence: PMID:17452316 These data are consistent with a model in which PCSK9 binding to EGF-A interferes with an acid-dependent conformational change required for receptor recycling. |
| GO:0005769 early endosome | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | ACCEPT | Summary: Early endosome localization with LDLR. Reason: PCSK9 sorts with LDLR to endosomes. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005770 late endosome | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | KEEP AS NON CORE | Summary: Late endosome localization en route to degradation. Reason: PCSK9 and LDLR co-localize in late endocytic compartments en route to lysosomes. Supporting Evidence: PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. |
| GO:0005770 late endosome | IDA PMID:18039658 The proprotein convertase PCSK9 induces the degradation of l... | KEEP AS NON CORE | Summary: Late endosome localization en route to degradation. Reason: PCSK9 and LDLR co-localize in late endocytic compartments en route to lysosomes. Supporting Evidence: PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. |
| GO:0005783 endoplasmic reticulum | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | ACCEPT | Summary: Autoprocessing occurs in the ER. Reason: Pro-PCSK9 autocleaves in the ER and accumulates there when it cannot exit. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Autoprocessing occurs in the ER. Reason: Pro-PCSK9 autocleaves in the ER and accumulates there when it cannot exit. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | ACCEPT | Summary: ER lumen site of autoprocessing. Reason: PCSK9 is a secretory protein processed in the ER lumen. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005794 Golgi apparatus | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | ACCEPT | Summary: Golgi transit of the secretory protein. Reason: PCSK9 traffics through the Golgi en route to secretion. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi transit of the secretory protein. Reason: PCSK9 traffics through the Golgi en route to secretion. Supporting Evidence: PMID:17461796 In cells lacking the LDLR, PCSK9 localized in the endoplasmic reticulum (ER). |
| GO:0005886 plasma membrane | IDA PMID:18799458 Annexin A2 is a C-terminal PCSK9-binding protein that regula... | KEEP AS NON CORE | Summary: Plasma membrane association via binding partners. Reason: PCSK9 is a soluble secreted protein that associates with the plasma membrane by binding LDLR or annexin A2; it is not an integral membrane protein. Supporting Evidence: PMID:18799458 Immunocytochemistry revealed that PCSK9 and AnxA2 co-localize at the cell surface, indicating a possible competition with the LDLR. |
| GO:0006508 proteolysis | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Proteolysis (autocatalytic). Reason: Correct only for the self-cleavage; PCSK9 does not degrade LDLR proteolytically, so this broad term should not be read as LDLR proteolysis. Supporting Evidence: PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0007041 lysosomal transport | IDA PMID:17452316 Binding of proprotein convertase subtilisin/kexin type 9 to ... | KEEP AS NON CORE | Summary: PCSK9 escorts LDLR to lysosomes. Reason: PCSK9 accompanies LDLR from endosomes to lysosomes, so it participates in lysosomal delivery of the receptor; this is captured more specifically by positive regulation of LDLR catabolic process. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0008236 serine-type peptidase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Serine-type peptidase activity (autocatalytic). Reason: Correct parent of the autocatalytic serine endopeptidase activity. Supporting Evidence: PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase |
| GO:0009267 cellular response to starvation | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PCSK9 expression falls with fasting. Reason: Fasting lowers hepatic PCSK9 mRNA and protein in mice; a nutritional regulation of the gene rather than a PCSK9 activity. Supporting Evidence: PMID:16407292 We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. |
| GO:0009267 cellular response to starvation | ISS PMID:16407292 Hepatic PCSK9 expression is regulated by nutritional status ... | KEEP AS NON CORE | Summary: PCSK9 expression falls with fasting. Reason: Fasting lowers hepatic PCSK9 mRNA and protein in mice; a nutritional regulation of the gene rather than a PCSK9 activity. Supporting Evidence: PMID:16407292 We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. |
| GO:0009986 cell surface | IDA PMID:17461796 The cellular trafficking of the secretory proprotein convert... | ACCEPT | Summary: PCSK9 binds LDLR at the cell surface. Reason: Extracellular PCSK9 binds LDLR at the hepatocyte surface before co-internalization. Supporting Evidence: PMID:17461796 In cell lines, PCSK9 also colocalized with the LDLR at the cell surface, requiring the presence of the C-terminal Cys/His-rich domain of PCSK9. |
| GO:0009986 cell surface | IEA GO_REF:0000044 | ACCEPT | Summary: PCSK9 binds LDLR at the cell surface. Reason: Extracellular PCSK9 binds LDLR at the hepatocyte surface before co-internalization. Supporting Evidence: PMID:17461796 In cell lines, PCSK9 also colocalized with the LDLR at the cell surface, requiring the presence of the C-terminal Cys/His-rich domain of PCSK9. |
| GO:0010989 negative regulation of low-density lipoprotein particle clearance | IDA PMID:17328821 Degradation of the LDL receptors by PCSK9 is not mediated by... | ACCEPT | Summary: Core process: PCSK9 lowers LDL clearance. Reason: By reducing hepatic LDLR, secreted PCSK9 reduces LDL uptake and raises plasma LDL cholesterol; gain-of-function alleles cause hypercholesterolemia and loss-of-function alleles lower LDL. Supporting Evidence: PMID:17328821 The ability of the conditioned medium to reduce the internalization of LDL was abolished by removal of recombinant PCSK9 from the conditioned medium by affinity chromatography. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0010989 negative regulation of low-density lipoprotein particle clearance | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | ACCEPT | Summary: Core process: PCSK9 lowers LDL clearance. Reason: By reducing hepatic LDLR, secreted PCSK9 reduces LDL uptake and raises plasma LDL cholesterol; gain-of-function alleles cause hypercholesterolemia and loss-of-function alleles lower LDL. Supporting Evidence: PMID:17328821 The ability of the conditioned medium to reduce the internalization of LDL was abolished by removal of recombinant PCSK9 from the conditioned medium by affinity chromatography. PMID:17080197 We conclude that secreted PCSK9 associates with the LDLR and reduces hepatic LDLR protein levels. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0016485 protein processing | IEA GO_REF:0000107 | ACCEPT | Summary: Protein processing (autoprocessing). Reason: Correct parent of protein autoprocessing. Supporting Evidence: PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 |
| GO:0016540 protein autoprocessing | IDA PMID:14622975 Functional characterization of Narc 1, a novel proteinase re... | ACCEPT | Summary: PCSK9 autoprocesses its prodomain. Reason: Autocatalytic intramolecular cleavage after the (L)VFAQ motif releases the prodomain from the catalytic domain; this maturation step precedes secretion. Supporting Evidence: PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 |
| GO:0016540 protein autoprocessing | IEA GO_REF:0000107 | ACCEPT | Summary: PCSK9 autoprocesses its prodomain. Reason: Autocatalytic intramolecular cleavage after the (L)VFAQ motif releases the prodomain from the catalytic domain; this maturation step precedes secretion. Supporting Evidence: PMID:14622975 Narc 1 undergoes autocatalytic intramolecular processing at the site LVFAQ/, resulting in the cleavage of its prosegment and the generation of an active proteinase PMID:12552133 human and mouse pro-NARC-1 are autocatalytically and intramolecularly processed into NARC-1 |
| GO:0019871 sodium channel inhibitor activity | IDA PMID:22493497 Regulation of epithelial sodium channel trafficking by propr... | KEEP AS NON CORE | Summary: PCSK9 lowers ENaC surface abundance; non-core. Reason: PCSK9 reduces ENaC current by reducing channel number via biosynthetic-pathway degradation, independent of catalysis. This is a non-catalytic down-regulation of a membrane protein analogous to its LDLR role, but peripheral to cholesterol regulation, and it acts on trafficking rather than gating. Supporting Evidence: PMID:22493497 This occurred through a decrease in ENaC protein at the cell surface and in the total cellular pool, an effect that did not require the catalytic activity of PCSK9. |
| GO:0022008 neurogenesis | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0022008 neurogenesis | ISS PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0030134 COPII-coated ER to Golgi transport vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: COPII vesicle export from ER. Reason: Plausible ER export carrier for a secreted protein; ortholog-derived detail. |
| GO:0030169 low-density lipoprotein particle binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PCSK9 associates with circulating LDL particles. Reason: A fraction of plasma PCSK9 associates with LDL, which modulates its activity; secondary to receptor binding. Supporting Evidence: PMID:18197702 When PCSK9 protein was incubated with total serum, it partially associated with LDL and HDL but not with VLDL. |
| GO:0030169 low-density lipoprotein particle binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PCSK9 associates with circulating LDL particles. Reason: A fraction of plasma PCSK9 associates with LDL, which modulates its activity; secondary to receptor binding. Supporting Evidence: PMID:18197702 When PCSK9 protein was incubated with total serum, it partially associated with LDL and HDL but not with VLDL. |
| GO:0030182 neuron differentiation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0030182 neuron differentiation | ISS PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | MARK AS OVER ANNOTATED | Summary: Developmental role inferred from expression pattern only. Reason: Transferred from rodent expression studies showing NARC-1 is expressed in proliferating and differentiating cells (liver, kidney, telencephalon). Expression is not participation, and PCSK9-deficient mice and humans with null alleles develop normally apart from low LDL cholesterol. Supporting Evidence: PMID:12552133 In situ hybridization and Northern blot analyses of NARC-1 expression during development in the adult and after partial hepatectomy revealed that it is expressed in cells that have the capacity to proliferate and differentiate. PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. |
| GO:0030547 signaling receptor inhibitor activity | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | MARK AS OVER ANNOTATED | Summary: PCSK9 inhibits LDLR, but LDLR is not a signaling receptor. Reason: PCSK9 antagonizes LDLR by targeting it for degradation. LDLR is an endocytic cargo receptor, not a signaling receptor, so 'signaling receptor inhibitor activity' misdescribes the target; the activity is captured by LDL particle receptor binding and positive regulation of LDLR catabolism. Supporting Evidence: PMID:22848640 Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). |
| GO:0031232 extrinsic component of external side of plasma membrane | IC PMID:17328821 Degradation of the LDL receptors by PCSK9 is not mediated by... | ACCEPT | Summary: Peripheral association with the cell surface via LDLR. Reason: Secreted PCSK9 binds the extracellular EGF-A repeat of LDLR, so it is an extrinsic component of the external side of the plasma membrane. Supporting Evidence: PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. |
| GO:0032802 low-density lipoprotein particle receptor catabolic process | IDA PMID:16912035 The proprotein convertase (PC) PCSK9 is inactivated by furin... | MODIFY | Summary: PCSK9 regulates, rather than executes, LDLR catabolism. Reason: PCSK9 enhances LDLR degradation without cleaving it (catalytic activity is dispensable); lysosomal proteases execute the catabolism. Positive regulation of LDL receptor catabolic process describes PCSK9's role more accurately. Proposed replacements: positive regulation of low-density lipoprotein particle receptor catabolic process Supporting Evidence: PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0032802 low-density lipoprotein particle receptor catabolic process | IDA PMID:18197702 Self-association of human PCSK9 correlates with its LDLR-deg... | MODIFY | Summary: PCSK9 regulates, rather than executes, LDLR catabolism. Reason: PCSK9 enhances LDLR degradation without cleaving it (catalytic activity is dispensable); lysosomal proteases execute the catabolism. Positive regulation of LDL receptor catabolic process describes PCSK9's role more accurately. Proposed replacements: positive regulation of low-density lipoprotein particle receptor catabolic process Supporting Evidence: PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0032805 positive regulation of low-density lipoprotein particle receptor catabolic process | IDA PMID:22081141 Mechanistic implications for LDL receptor degradation from t... | ACCEPT | Summary: Core process: PCSK9 promotes lysosomal degradation of the LDL receptor. Reason: PCSK9 bound to LDLR is co-internalized and redirects the receptor from recycling to lysosomal degradation, lowering hepatocyte LDLR number. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. PMID:22081141 Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. PMID:22848640 Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). |
| GO:0032805 positive regulation of low-density lipoprotein particle receptor catabolic process | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | ACCEPT | Summary: Core process: PCSK9 promotes lysosomal degradation of the LDL receptor. Reason: PCSK9 bound to LDLR is co-internalized and redirects the receptor from recycling to lysosomal degradation, lowering hepatocyte LDLR number. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. PMID:22081141 Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. PMID:22848640 Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). |
| GO:0032869 cellular response to insulin stimulus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: PCSK9 expression is induced by insulin. Reason: Insulin up-regulates hepatic PCSK9 transcription through SREBP-1c; this is regulation of the gene, not a PCSK9 activity. Supporting Evidence: PMID:16407292 PCSK9 mRNA increased by 4-5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. |
| GO:0032869 cellular response to insulin stimulus | ISS PMID:12552133 The secretory proprotein convertase neural apoptosis-regulat... | KEEP AS NON CORE | Summary: PCSK9 expression is induced by insulin. Reason: Insulin up-regulates hepatic PCSK9 transcription through SREBP-1c; this is regulation of the gene, not a PCSK9 activity. Supporting Evidence: PMID:16407292 PCSK9 mRNA increased by 4-5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. |
| GO:0034185 apolipoprotein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: PCSK9 interacts with apoB. Reason: Endogenous PCSK9 interacts with apoB in hepatocytes and may affect apoB secretion; a secondary, less established role. Supporting Evidence: PMID:22580899 Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in hepatocytes. |
| GO:0034185 apolipoprotein binding | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: PCSK9 interacts with apoB. Reason: Endogenous PCSK9 interacts with apoB in hepatocytes and may affect apoB secretion; a secondary, less established role. Supporting Evidence: PMID:22580899 Importantly, we demonstrated that endogenous PCSK9 interacted with apoB in hepatocytes. |
| GO:0034189 very-low-density lipoprotein particle binding | IEA GO_REF:0000107 | REMOVE | Summary: VLDL particle binding is contradicted for human PCSK9. Reason: Ortholog-transferred annotation. Human PCSK9 incubated with serum, and PCSK9 in transgenic mice, associated with LDL and HDL but not with VLDL. Supporting Evidence: PMID:18197702 When PCSK9 protein was incubated with total serum, it partially associated with LDL and HDL but not with VLDL. |
| GO:0034189 very-low-density lipoprotein particle binding | ISS GO_REF:0000024 | REMOVE | Summary: VLDL particle binding is contradicted for human PCSK9. Reason: Ortholog-transferred annotation. Human PCSK9 incubated with serum, and PCSK9 in transgenic mice, associated with LDL and HDL but not with VLDL. Supporting Evidence: PMID:18197702 When PCSK9 protein was incubated with total serum, it partially associated with LDL and HDL but not with VLDL. |
| GO:0034190 apolipoprotein receptor binding | IDA PMID:18039658 The proprotein convertase PCSK9 induces the degradation of l... | KEEP AS NON CORE | Summary: PCSK9 also binds and degrades ApoER2. Reason: ApoER2 is an LDLR-family receptor targeted by PCSK9; real but secondary. Supporting Evidence: PMID:18039658 In this study, we show that two of the closest family members to LDLR are also PCSK9 targets. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-6784729 | KEEP AS NON CORE | Summary: Endolysosome membrane association with LDLR. Reason: As for lysosome; degradative itinerary. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0036020 endolysosome membrane | TAS Reactome:R-HSA-6784738 | KEEP AS NON CORE | Summary: Endolysosome membrane association with LDLR. Reason: As for lysosome; degradative itinerary. Supporting Evidence: PMID:17452316 As a consequence, the LDLR is rerouted from the endosome to the lysosome where it is degraded. |
| GO:0042632 cholesterol homeostasis | IDA PMID:16912035 The proprotein convertase (PC) PCSK9 is inactivated by furin... | ACCEPT | Summary: PCSK9 is a major regulator of cholesterol homeostasis. Reason: Human gain- and loss-of-function alleles shift plasma LDL cholesterol in opposite directions through hepatic LDLR abundance. Supporting Evidence: PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: PCSK9 is a major regulator of cholesterol homeostasis. Reason: Human gain- and loss-of-function alleles shift plasma LDL cholesterol in opposite directions through hepatic LDLR abundance. Supporting Evidence: PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. |
| GO:0042632 cholesterol homeostasis | IMP PMID:17170371 A novel loss of function mutation of PCSK9 gene in white sub... | ACCEPT | Summary: PCSK9 is a major regulator of cholesterol homeostasis. Reason: Human gain- and loss-of-function alleles shift plasma LDL cholesterol in opposite directions through hepatic LDLR abundance. Supporting Evidence: PMID:17170371 In African-Americans two nonsense mutations resulting in loss of function of PCSK9 are associated with a 30% to 40% reduction of plasma low-density lipoprotein cholesterol. PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. |
| GO:0043523 regulation of neuron apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Neuronal apoptosis regulation; non-core. Reason: Based on overexpression studies in neurons; peripheral to the lipoprotein role. Supporting Evidence: PMID:17051583 Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. |
| GO:0043523 regulation of neuron apoptotic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal apoptosis regulation; non-core. Reason: Based on overexpression studies in neurons; peripheral to the lipoprotein role. Supporting Evidence: PMID:17051583 Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. |
| GO:0043525 positive regulation of neuron apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Pro-apoptotic effect of overexpressed NARC-1 in cultured neurons. Reason: Overexpression in cerebellar granule neurons increased cell death; mechanism unclear and physiological relevance uncertain. Supporting Evidence: PMID:17051583 Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. |
| GO:0043525 positive regulation of neuron apoptotic process | IMP PMID:17051583 Proapoptotic effects of NARC 1 (= PCSK9), the gene encoding ... | KEEP AS NON CORE | Summary: Pro-apoptotic effect of overexpressed NARC-1 in cultured neurons. Reason: Overexpression in cerebellar granule neurons increased cell death; mechanism unclear and physiological relevance uncertain. Supporting Evidence: PMID:17051583 Wild-type NARC 1 was found to have substantial proapoptotic effects that were only partially reversible by BAF. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:18039658 The proprotein convertase PCSK9 induces the degradation of l... | KEEP AS NON CORE | Summary: Perinuclear region (Golgi/endosomes). Reason: Perinuclear staining reflects Golgi and late endosomal compartments; uninformative. |
| GO:0050750 low-density lipoprotein particle receptor binding | IDA PMID:17080197 Secreted PCSK9 decreases the number of LDL receptors in hepa... | ACCEPT | Summary: Core function: PCSK9 binds the EGF-A repeat of the LDL receptor. Reason: Secreted PCSK9 binds the first EGF-like repeat of LDLR at the hepatocyte surface; the complex is internalized and, because PCSK9 blocks the acid-dependent conformational change needed for recycling, LDLR is diverted to lysosomes. This binding, not proteolysis, is the basis of PCSK9 control of plasma LDL. Supporting Evidence: PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0050750 low-density lipoprotein particle receptor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Core function: PCSK9 binds the EGF-A repeat of the LDL receptor. Reason: Secreted PCSK9 binds the first EGF-like repeat of LDLR at the hepatocyte surface; the complex is internalized and, because PCSK9 blocks the acid-dependent conformational change needed for recycling, LDLR is diverted to lysosomes. This binding, not proteolysis, is the basis of PCSK9 control of plasma LDL. Supporting Evidence: PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0050750 low-density lipoprotein particle receptor binding | IPI PMID:17452316 Binding of proprotein convertase subtilisin/kexin type 9 to ... | ACCEPT | Summary: Core function: PCSK9 binds the EGF-A repeat of the LDL receptor. Reason: Secreted PCSK9 binds the first EGF-like repeat of LDLR at the hepatocyte surface; the complex is internalized and, because PCSK9 blocks the acid-dependent conformational change needed for recycling, LDLR is diverted to lysosomes. This binding, not proteolysis, is the basis of PCSK9 control of plasma LDL. Supporting Evidence: PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0050750 low-density lipoprotein particle receptor binding | IPI PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | ACCEPT | Summary: Core function: PCSK9 binds the EGF-A repeat of the LDL receptor. Reason: Secreted PCSK9 binds the first EGF-like repeat of LDLR at the hepatocyte surface; the complex is internalized and, because PCSK9 blocks the acid-dependent conformational change needed for recycling, LDLR is diverted to lysosomes. This binding, not proteolysis, is the basis of PCSK9 control of plasma LDL. Supporting Evidence: PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. PMID:17080197 Coimmunoprecipitation and ligand blotting studies indicated that PCSK9 and LDLR directly associate; both proteins colocalized to late endocytic compartments. PMID:18039658 Such PCSK9-induced degradation does not require its catalytic activity. |
| GO:0070326 very-low-density lipoprotein particle receptor binding | IDA PMID:18039658 The proprotein convertase PCSK9 induces the degradation of l... | KEEP AS NON CORE | Summary: PCSK9 also binds and degrades VLDLR. Reason: PCSK9 targets the LDLR-family members VLDLR and ApoER2 for degradation as well as LDLR; real but secondary to hepatic LDLR regulation. Supporting Evidence: PMID:18039658 In this study, we show that two of the closest family members to LDLR are also PCSK9 targets. |
| GO:0141110 transporter inhibitor activity | IDA PMID:16912035 The proprotein convertase (PC) PCSK9 is inactivated by furin... | UNDECIDED | Summary: Transporter inhibitor activity; could not be verified. Reason: The cited study is abstract-only in the cache and its abstract concerns furin/PC5/6A processing of PCSK9; no transporter inhibition is described. The basis of the curator's annotation could not be checked. Supporting Evidence: PMID:16912035 it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. |
| GO:1903783 negative regulation of sodium ion import across plasma membrane | IDA PMID:22493497 Regulation of epithelial sodium channel trafficking by propr... | KEEP AS NON CORE | Summary: ENaC-mediated sodium import reduced; non-core. Reason: Consequence of reduced ENaC abundance at the cell surface; demonstrated in oocytes and epithelia. Supporting Evidence: PMID:22493497 This occurred through a decrease in ENaC protein at the cell surface and in the total cellular pool, an effect that did not require the catalytic activity of PCSK9. |
| GO:1905601 negative regulation of receptor-mediated endocytosis involved in cholesterol transport | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | KEEP AS NON CORE | Summary: Reduced LDL uptake through loss of receptors. Reason: PCSK9 lowers LDL endocytosis by reducing receptor number, so the effect on endocytosis is indirect; negative regulation of LDL clearance captures the role more directly. Supporting Evidence: PMID:17328821 The ability of the conditioned medium to reduce the internalization of LDL was abolished by removal of recombinant PCSK9 from the conditioned medium by affinity chromatography. |
| GO:1990666 PCSK9-LDLR complex | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | ACCEPT | Summary: PCSK9 forms a complex with LDLR. Reason: The PCSK9-LDLR complex (PCSK9 catalytic domain bound to LDLR EGF-A) is the functional unit that diverts LDLR to lysosomes. Supporting Evidence: PMID:22081141 Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling. PMID:17452316 Recombinant human PCSK9 interacted in a sequence-specific manner with the first epidermal growth factor-like repeat (EGF-A) in the EGF homology domain of the human LDLR. |
| GO:1990667 PCSK9-AnxA2 complex | IDA PMID:22848640 Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-... | KEEP AS NON CORE | Summary: PCSK9-annexin A2 complex inhibits PCSK9. Reason: Annexin A2 binds the PCSK9 C-terminal domain and inhibits its LDLR-degrading activity; a regulatory complex acting on PCSK9. Supporting Evidence: PMID:22848640 We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. PMID:24808179 Annexin A2 (AnxA2) was reported to be an extracellular endogenous inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9) activity on cell-surface LDL receptor degradation. |
| GO:1990667 PCSK9-AnxA2 complex | IPI PMID:24808179 Annexin A2 reduces PCSK9 protein levels via a translational ... | KEEP AS NON CORE | Summary: PCSK9-annexin A2 complex inhibits PCSK9. Reason: Annexin A2 binds the PCSK9 C-terminal domain and inhibits its LDLR-degrading activity; a regulatory complex acting on PCSK9. Supporting Evidence: PMID:22848640 We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. PMID:24808179 Annexin A2 (AnxA2) was reported to be an extracellular endogenous inhibitor of proprotein convertase subtilisin kexin type 9 (PCSK9) activity on cell-surface LDL receptor degradation. |
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