Human apolipoprotein A-I (apoA-I) is a major component of high-density lipoprotein and plays a critical role in reverse cholesterol transport. The 28 kDa protein (243 residues) is composed of an N-terminal (NT) helix bundle domain and a less structured C-terminal (CT) domain. The CT domain contains helices responsible for high-affinity binding to phospholipids to initiate apoA-I lipidation and mediates self-association. However, previous studies suggested a similar role for the NT helices. Recently, a chimera system was developed in which insect apolipophorin III (apoLp-III) was used as a scaffold to present the CT domain of apoA-I, which then acquired lipid binding and self-association properties similar to apoA-I. This chimera system was exploited to better understand the role of NT and CT helices of apoA-I in lipid binding and self-association. Four novel chimeras were designed, in which residues 1-43 or 44-65 of apoA-I were attached to the NT end of apoLp-III, and CT domain residues 209-243 or 220-243 of apoA-I were attached to the CT end of apoLp-III. The chimeras displayed -helical contents similar to apoLp-III, indicating that the structure of the parent apoLp-III was maintained. All chimeras were able to solubilize phospholipid vesicles much faster compared to apoLp-III. The chimera apoLp-III/apoA-I(209-243) formed oligomers similar to apoA-I, while chimeras with NT helices of apoA-I and CT helix 220-243 were not able to induce self-association. Thus, NT and CT helices of apoA-I provide high-affinity sites for phospholipid binding, indicating the potential to initiate lipid binding, while residues responsible for self-association are located primarily in the CT domain of apoA-I.
|Commitee:||Narayanaswami, Vasanthy, Bhandari, Deepali|
|School:||California State University, Long Beach|
|Department:||Chemistry and Biochemistry|
|School Location:||United States -- California|
|Source:||MAI 82/8(E), Masters Abstracts International|
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