Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1.
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.
Zhu
Jian
J
Pfizer Global Research and Development, Department of Cardiovascular and Metabolic Diseases, Groton, CT 06340, USA.
Gardner
Joseph
J
Pullinger
Clive R
CR
Kane
John P
JP
Thompson
John F
JF
Francone
Omar L
OL
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism*; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000097:blood; D006224:Cricetinae; D003412:Cricetulus; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011110:Polymorphism, Genetic; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C491553:PCOLCE2 protein, human; D011498:Protein Precursors; D055395:Bone Morphogenetic Protein 1