title: Crystal structure of Δ(185-243)ApoA-I suggests a mechanistic framework for the protein adaptation to the changing lipid load in good cholesterol: from flatland to sphereland via double belt, belt buckle, double hairpin and trefoil/tetrafoil.
abstract: Apolipoprotein A-I (apoA-I) is the major protein of plasma high-density lipoproteins (HDLs), macromolecular assemblies of proteins and lipids that remove cell cholesterol and protect against atherosclerosis. HDL heterogeneity, large size (7.7-12 nm), and ability to exchange proteins have prevented high-resolution structural analysis. Low-resolution studies showed that two apoA-I molecules form an antiparallel α-helical "double belt" around an HDL particle. The atomic-resolution structure of the C-terminal truncated lipid-free Δ(185-243)apoA-I, determined recently by Mei and Atkinson, provides unprecedented new insights into HDL structure-function. It allows us to propose a molecular mechanism for the adaptation of the full-length protein to increasing lipid load during cholesterol transport. ApoA-I conformations on small, midsize, and large HDLs are proposed based on the tandem α-helical repeats and the crystal structure of Δ(185-243)apoA-I and are validated by comparison with extensive biophysical data reported by many groups. In our models, the central half of the double belt ("constant" segment 66-184) is structurally conserved while the N- and C-terminal half ("variable" segments 1-65 and 185-243) rearranges upon HDL growth. This includes incremental unhinging of the N-terminal bundle around two flexible regions containing G39 and G65 to elongate the belt, along with concerted swing motion of the double belt around G65-P66 and G185-G186 hinges that are aligned on various-size particles, to confer two-dimensional surface curvature to spherical HDLs. The proposed conformational ensemble integrates and improves several existing HDL models. It helps provide a structural framework necessary to understand functional interactions with over 60 other HDL-associated proteins and, ultimately, improve the cardioprotective function of HDL.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA. gursky@bu.edu
authors.forename: Olga
authors.initials: O
authors.lastname: Gursky
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry*; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008075:Lipoproteins, HDL / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D017433:Protein Structure, Secondary
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D002784:Cholesterol