NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol
| Autor: | Suzanne, Benjannet, David, Rhainds, Rachid, Essalmani, Janice, Mayne, Louise, Wickham, Weijun, Jin, Marie-Claude, Asselin, Josée, Hamelin, Mathilde, Varret, Delphine, Allard, Mélanie, Trillard, Marianne, Abifadel, Angie, Tebon, Alan D, Attie, Daniel J, Rader, Catherine, Boileau, Louise, Brissette, Michel, Chrétien, Annik, Prat, Nabil G, Seidah |
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| Rok vydání: | 2004 |
| Předmět: |
Heterozygote
DNA Complementary Time Factors Blotting Western Hypercholesterolemia Mutation Missense Mice Transgenic Cell Separation Endoplasmic Reticulum Transfection Ammonium Chloride Catalysis Mass Spectrometry Adenoviridae Cell Line Mice Animals Humans Gene Silencing Lymphocytes RNA Messenger Apolipoproteins B Enzyme Precursors Binding Sites Cell Membrane Serine Endopeptidases Cholesterol LDL Flow Cytometry Protein Structure Tertiary Mice Inbred C57BL Cholesterol Receptors LDL Mutation Calcium Female Proprotein Convertases Proprotein Convertase 9 Gene Deletion |
| Zdroj: | The Journal of biological chemistry. 279(47) |
| ISSN: | 0021-9258 |
| Popis: | The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca2+-independent and that within the zymogen autocatalytic processing site SSVFAQ [downward arrow]SIP Val at P4 and Pro at P3' are critical. The S127R and D374Y mutations result in approximately 50-60% andor =98% decrease in zymogen processing, respectively. In contrast, the double [D374Y + N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mm ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal approximately 9-fold increase in circulating LDL cholesterol, while in LDLR-/- mice a delayed approximately 2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion. |
| Databáze: | OpenAIRE |
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