Journal of Biological Chemistry
Volume 279, Issue 47, 19 November 2004, Pages 48865-48875
Journal home page for Journal of Biological Chemistry

Protein Synthesis, Post-Translation Modification, and Degradation
NARC-1/PCSK9 and Its Natural Mutants: ZYMOGEN CLEAVAGE AND EFFECTS ON THE LOW DENSITY LIPOPROTEIN (LDL) RECEPTOR AND LDL CHOLESTEROL*

https://doi.org/10.1074/jbc.M409699200Get rights and content
Under a Creative Commons license
open access

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↓SIP Val at P4 and Pro at P3′ are critical. The S127R and D374Y mutations result in ∼50–60% and ≥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 ∼9-fold increase in circulating LDL cholesterol, while in LDLR(–/–) mice a delayed ∼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.

Cited by (0)

*

This work was supported in part by Canadian Institutes of Health Research Grants MOP 36496 and MOP 44362, Group Grant MGC-64518, and National Institutes of Health Grant HL56593. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b

Supported by a Natural Sciences and Engineering Council of Canada fellowship.

f

Supported by a grant from the Ministère de l'Enseignement Supérieur et de la Recherche, France.

g

Supported by a grant from the Nouvelle Société Française d'Athérosclérose, France.