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Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I.


ABSTRACT: 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 ?(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.

SUBMITTER: Gursky O 

PROVIDER: S-EPMC3826673 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Structural basis for distinct functions of the naturally occurring Cys mutants of human apolipoprotein A-I.

Gursky Olga O   Jones Martin K MK   Mei Xiaohu X   Segrest Jere P JP   Atkinson David D  

Journal of lipid research 20130913 12


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(185-24  ...[more]

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