The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.
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Benjannet S, Rhainds D, Hamelin J, Nassoury N, Seidah NG
The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.
J Biol Chem. 2006 Oct 13;281(41):30561-72. Epub 2006 Aug 15.
- PubMed ID
- 16912035 [ View in PubMed]
- Abstract
PCSK9 is the ninth member of the proprotein convertase (PC) family. Some of its natural mutations have been genetically associated with the development of a dominant form of familial hyper- or hypocholesterolemia. The exact mechanism of action of PCSK9 is not clear, although it is known to enhance the intracellular degradation of the low density lipoprotein (LDL) receptor in acidic compartments, likely the endosomes/lysosomes. We analyzed the post-translational modifications of PCSK9 and show that it is sulfated within its prosegment at Tyr38. We also examined the susceptibility of PCSK9 to proteolytic cleavage by the other members of the PC family. The data show that the natural gain-of-function mutations R218S, F216L, and D374Y associated with hypercholesterolemia result in total or partial loss of furin/PC5/6A processing at the motif RFHR218 downward arrow. In contrast, the loss-of-function mutations A443T and C679X lead either to the lack of trans-Golgi network/recycling endosome localization and an enhanced susceptibility to furin cleavage (A443T) or to the inability of PCSK9 to exit the endoplasmic reticulum (C679X). Furthermore, we report the presence of both native and furin-like cleaved forms of PCSK9 in circulating human plasma. Thus, we propose that PCSK9 levels are finely regulated by the basic amino acid convertases furin and PC5/6A. The latter may reduce the lifetime of this proteinase and its ability to degrade the cell-surface LDL receptor, thereby regulating the levels of circulating LDL cholesterol.