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J. Biol. Chem., Vol. 281, Issue 41, 30561-30572, October 13, 2006

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The Proprotein Convertase (PC) PCSK9 Is Inactivated by Furin and/or PC5/6A

FUNCTIONAL CONSEQUENCES OF NATURAL MUTATIONS AND POST-TRANSLATIONAL MODIFICATIONS^*

From the Laboratory of Biochemical Neuroendocrinology, Clinical Research Institute of Montreal, Montreal, Quebec H2W 1R7, Canada

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. 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.

Received for publication, July 7, 2006 , and in revised form, August 14, 2006.

^* This work was supported in part by Canadian Institutes of Health Research Grants MOP-36496 and MGP-44363 (to N. G. S.) and by the Strauss Foundation. 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.

¹ Recipient of a postdoctoral scholarship from the Natural Sciences and Engineering Research Council of Canada.

² Recipient of a Fonds Québécois de la Recherche sur la Nature et les Technologies postdoctoral fellowship.

³ To whom correspondence should be addressed: Laboratory of Biochemical Neuroendocrinology, Clinical Research Inst. of Montreal, 110 Pine Ave. West, Montreal, Quebec H2W 1R7, Canada. Tel.: 514-987-5609; Fax: 514-987-5542; E-mail: seidahn{at}ircm.qc.ca.

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