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

Abstract

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, J., J. Gardner, C. R. Pullinger, J. P. Kane, J. F. Thompson, and O. L. Francone. Regulation of apoAI processing by procollagen C-proteinase enhancer-2 and bone morphogenetic protein-1. J. Lipid Res. 2009Res. . 50: 1330Res. -1339 Supplementary key words apoAI synthesisDyslipidemia is a major risk factor for premature development of cardiovascular disease. A high ratio of atherogenic lipoproteins (VLDL, LDL, and IDL) to HDL leads to endothelial dysfunction, focal inflammation, and oxidative stress resulting in the initiation and progression of atherosclerosis. Plasma levels of HDL are inversely correlated with the onset of coronary artery disease as attested to by the outcome of several large prospective epidemiological studies (1, 2). The protective effect of HDL is due, at least in part, to the role of this class of lipoproteins in modulating inflammation and mediating cholesterol transport from peripheral cells to sites of reutilization and degradation (3). Apolipoprotein AI (apoAI); the main protein moiety of HDL; drives the formation and speciation of HDL resulting in a very heterogeneous class of particles, particularly with respect to particle size, density, protein content, and surface charge, which determines their functional role and metabolic fate (4). Understanding the processes involved in the synthesis and maturation of HDL species will ultimately provide the knowledge required to understand and appreciate the functional significance of each of the HDL subpopulations and their impact in the development of atherosclerosis.The importance of HDL-C in disease makes it amenable to candidate-gene an...

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“…However, the extent of collagen fibril abnormalities in tissues of PCPE1-null mice (46) suggests possible additional roles for PCPEs. Suggestive but inconclusive genetic studies have implicated PCPE2 in modulating serum levels of HDL, whereas biochemical studies have shown PCPE2 to be associated with serum HDL and to be capable of binding both pro-ApoA1 and BMP1 and perhaps enhancing proApoA1 processing by BMP1 in vitro (88). In vivo roles for PCPE2 in modulating HDL levels and pro-ApoA1 processing are supported by recent findings of decreased pro-ApoA1 processing and changes to HDL levels and properties in PCPE2-null mice (89).…”

Cubbing in proapolipoprotein maturation

“…The CUB domains facilitate protein-protein interactions, in this case BMP-1 and PCPE1 to allow for the productive cleavage of the C-terminal prosequence from procollagen. The cleavage of pro-apoA-I is by a very similar process involving BMP-1 ( 5 ) and PCPE2 forming a complex with the proapoprotein, again via the CUB domains of the fi rst two components ( 6 ). Binding studies suggest that the order of addition of these components to the complex may favor the association of pro-apoA-I with BMP-1 followed by the addition of PCPE2.…”

Analysis of differentially expressed gene fragments in the head kidney of lipopolysaccharide-stimulated Malabar grouper (Epinephelus malabaricus)

“…Procollagen C-endopeptidase enhancer (pcpe) can regulate the level of high-density lipoprotein (HDL) particles in vivo (Zhu et al 2009). HDL particles have the function of anti-inflammatory, anti-aggregative and antioxidant properties Stein 1999, Fredenrich andBayer 2003).…”