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Journal of Lipid Research, Vol. 50, 1330-1339, July 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1

Jian Zhu^*, Joseph Gardner^*, Clive R. Pullinger^,, John P. Kane, John F. Thompson^2,* and Omar L. Francone^1,*

^* Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Groton, CT 06340
Cardiovascular Research Institute, University of California, San Francisco, CA 94143
Department of Physiological Nursing, University of California, San Francisco, CA 94143
² Present address of J. F. Thompson: Helicos BioSciences, One Kendall Square Building 700, Cambridge, MA 02139.

Published, JLR Papers in Press, February 23, 2009.

¹ To whom correspondence should be addressed. e-mail: omar.l.francone{at}pfizer.com

Given the increased prevalence of cardiovascular disease in the world, the search for genetic variations controlling the levels of risk factors associated with the development of the disease continues. Multiple genetic association studies suggest the involvement of procollagen C-proteinase enhancer-2 (PCPE2) in modulating HDL-C levels. Therefore biochemical and mechanistic studies were undertaken to determine whether there might be a basis for a role of PCPE2 in HDL biogenesis. Our studies indicate that PCPE2 accelerates the proteolytic processing of pro-apolipoprotein (apo) AI by enhancing the cleavage of the hexapeptide extension present at the N terminus of apoAI. Surface Plasmon Resonance and immunoprecipitation studies indicate that PCPE2 interacts with BMP-1 and pro-apoAI to form a ternary pro-apoAI/BMP-1/PCPE2 complex. The most favorable interaction among these proteins begins with the association of BMP-1 to pro-apoAI followed by the binding of PCPE2 which further stabilizes the complex. PCPE2 resides, along with apoAI, on the HDL fraction of lipoproteins in human plasma supporting a relationship between HDL and PCPE2. Taken together, the findings from our studies identify a new player in the regulation of apoAI post-translational processing and open a new avenue to the study of mechanisms involved in the regulation of apoAI synthesis, HDL levels, and potentially, cardiovascular disease.

Supplementary key words apoAI synthesis • BMP-1 • cardiovascular disease • genetics • HDL • PCPE2

Abbreviations: ApoAI, apolipoprotein AI; BMP-1, bone morphogenetic protein-1; CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CUB, complement C1r/C1s, Uegf, Bmp1; EST, expressed sequence tag; FPLC, fast-protein liquid chromatography; HuAI, transgenic mice expressing human apoAI; PCPE2, procollagen C-proteinase enhancer-2; SNP, single-nucleotide polymorphism

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