title: The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications.
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.
authors.affiliation: Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Benjannet
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.forename: Josée
authors.initials: J
authors.lastname: Hamelin
authors.forename: Nasha
authors.initials: N
authors.lastname: Nassoury
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D045683:Furin / Q000737:chemistry*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D045702:Proprotein Convertase 5 / Q000737:chemistry*; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011499:Protein Processing, Post-Translational; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D021601:trans-Golgi Network / Q000378:metabolism
chemical_list: D008077:Lipoproteins, LDL; C472125:PCSK9 protein, human; D045702:Proprotein Convertase 5; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D045683:Furin