文章基本信息

标题：Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I
本地全文：下载
作者：Olga Gursky ; Martin K. Jones ; Xiaohu Mei 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2013
卷号：54
期号：12
页码：3244-3257
DOI：10.1194/jlr.R037911
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：HDL removes cell cholesterol and protects against atherosclerosis. ApoA-I provides a flexible structural scaffold and an important functional ligand on the HDL surface. We propose structural models for apoA-I_Milano (R173C) and apoA-I_Paris (R151C) mutants that show high cardioprotection despite low HDL levels. Previous studies established that two apoA-I molecules encircle HDL in an antiparallel, helical double-belt conformation. Recently, we solved the atomic structure of lipid-free Δ(185–243)apoA-I and proposed a conformational ensemble for apoA-I_WT on HDL. Here we modify this ensemble to understand how intermolecular disulfides involving C173 or C151 influence protein conformation. The double-belt conformations are modified by belt rotation, main-chain unhinging around Gly, and Pro-induced helical bending, and they are verified by comparison with previous experimental studies and by molecular dynamics simulations of apoA-I_Milano homodimer. In our models, the molecular termini repack on various-sized HDL, while packing around helix-5 in apoA-I_WT, helix-6 in apoA-I_Paris, or helix-7 in apoA-I_Milano homodimer is largely conserved. We propose how the disulfide-induced constraints alter the protein conformation and facilitate dissociation of the C-terminal segment from HDL to recruit additional lipid. Our models unify previous studies of apoA-I_Milano and demonstrate how the mutational effects propagate to the molecular termini, altering their conformations, dynamics, and function.
关键词：Milano and Paris mutations ; double-belt and trefoil/tetrafoil conformations ; protein-lipid interactions ; protein dynamics and function ; atherosclerosis