Disruption of the C-terminal helix by single amino acid deletion is directly responsible for impaired cholesterol efflux ability of apolipoprotein A-I Nichinan

作者：Kono Momoe; Tanaka Toshitaka; Tanaka Masafumi; Vedhachalam Charulatha; Chetty Palaniappan S; Nguyen David; Dhanasekaran Padmaja; Lund Katz Sissel; Phillips Michael C; Saito Hiroyuki^*

来源：The Journal of Lipid Research, 2010, 51(4): 809-818.

DOI：10.1194/jlr.M002113

• natural mutation
• high density lipoprotein
• tertiary structure
• lipid binding
• peptide

Apolipoprotein A-I (apoA-I) Nichinan, a naturally occurring variant with Delta E235 in the C terminus, is associated with low plasma HDL levels. Here, we investigated the tertiary structure, lipid-binding properties, and ability to induce cellular cholesterol efflux of apoA-I Nichinan and its C-terminal peptide. Thermal and chemical denaturation experiments demonstrated that the Delta E235 mutation decreased the protein stability compared with wild type (WT). ApoA-I Nichinan exhibited capabilities to bind to or solubilize lipid vesicles that are intermediate to that of WT and a L230P/L233P/Y236P variant in which the C-terminal alpha-helix folding is completely disrupted and forms relatively larger and unstable discoidal complexes, indicating that perturbation of the C-terminal alpha-helical structure by the Delta E235 mutation leads to reduced lipid binding. Supporting this, apoA-I 209241/Delta E235 peptide showed significantly decreased ability to form alpha-helix both in the lipid-free and lipid-bound states, and reduced efficiency to solubilize vesicles. In addition, both apoA-I Nichinan and its C-terminal peptide exhibited reduced activity in ABCA1-mediated cellular cholesterol efflux. Thus, the disruption of the ability of the C-terminal region to form alpha-helix caused by the E235 deletion appears to be the important determinant of impaired lipid binding and cholesterol efflux ability and, consequently, the low plasma HDL levels of apoA-I Nichinan probands.-Kono, M., T. Tanaka, M. Tanaka, C. Vedhachalam, P. S. Chetty, D. Nguyen, P. Dhanasekaran, S. Lund-Katz, M. C. Phillips, and H. Saito. Disruption of the C-terminal helix by single amino acid deletion is directly responsible for impaired cholesterol efflux ability of apolipoprotein A-I Nichinan. J. Lipid Res. 2010. 51: 809-818.

• 出版日期2010-4