Autor: |
Momoe Kono, Toshitaka Tanaka, Masafumi Tanaka, Charulatha Vedhachalam, Palaniappan S. Chetty, David Nguyen, Padmaja Dhanasekaran, Sissel Lund-Katz, Michael C. Phillips, Hiroyuki Saito |
Jazyk: |
angličtina |
Rok vydání: |
2010 |
Předmět: |
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Zdroj: |
Journal of Lipid Research, Vol 51, Iss 4, Pp 809-818 (2010) |
Druh dokumentu: |
article |
ISSN: |
0022-2275 |
DOI: |
10.1194/jlr.M002113 |
Popis: |
Apolipoprotein A-I (apoA-I) Nichinan, a naturally occurring variant with ΔE235 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 ΔE235 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 α-helix folding is completely disrupted and forms relatively larger and unstable discoidal complexes, indicating that perturbation of the C-terminal α-helical structure by the ΔE235 mutation leads to reduced lipid binding. Supporting this, apoA-I 209-241/ΔE235 peptide showed significantly decreased ability to form α-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 α-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. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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