Although plasma high-density lipoproteins (HDL) have been implicated in several cardioprotective pathways, the physiologic role of apolipoprotein (apo) A-II, the second most abundant of the HDL proteins, remains ambiguous. Human apo A-II is distinguished from most other species by a single cysteine (Cys6), which forms a disulfide bond with other cysteine-containing apos. In human plasma, nearly all apo A-II occurs as disulfide-linked homodimers of 17.4 kDa. Although dimerization is an important determinant of human apo A-II metabolism, its mechanism and the plasma and/or cellular sites of its dimerization are not known. Using SDS-PAGE and densitometry we investigated the kinetics of apo A-II dimerization and observed a slow (t1/2 = ∼10 days), second-order process in Tris-buffered saline. In 3 M guanidine hydrochloride, which disrupts apo A-II secondary structure and self-association, the rate was 3-fold slower. In contrast, lipid surfaces that promote apo A-II α-helix formation and lipophilic interaction profoundly enhanced the rate. Reassembled HDL increased the second-order rate constant k2 by 7500-fold, unilamellar 1-palmitoyl-2-oleoylphosphatidylcholine vesicles increased k2 850-fold, and physiological concentrations of human serum albumin increased k2 220-fold. Thus, while dimerization of apo A-II in aqueous buffer is too slow to account for the high fraction of dimer found in plasma, lipids and proteins "catalyze" dimer formation, a process that could occur either intracellularly prior to secretion or in the plasma compartment following secretion. These data suggest that formation of disulfide links within or between polypeptide chains can be controlled, in part, by coexisting lipids and proteins.
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