title: 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 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.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Olga
authors.initials: O
authors.lastname: Gursky
authors.forename: Martin K
authors.initials: MK
authors.lastname: Jones
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Mei
authors.forename: Jere P
authors.initials: JP
authors.lastname: Segrest
authors.forename: David
authors.initials: D
authors.lastname: Atkinson
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D016632:Apolipoprotein A-I; D003545:Cysteine
keywords: Milano and Paris mutations; atherosclerosis; double-belt and trefoil/tetrafoil conformations; protein dynamics and function; protein-lipid interactions
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