title: Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.
abstract: Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1-184] forms a helix bundle while the C-terminal domain [185-243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Mei
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA. Electronic address: atkinson@bu.edu.
authors.forename: David
authors.initials: D
authors.lastname: Atkinson
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D001053:Apolipoproteins / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002784:Cholesterol / Q000493:pharmacokinetics; D006801:Humans; D008055:Lipids; D008075:Lipoproteins, HDL / Q000096:biosynthesis*; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology
chemical_list: D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008055:Lipids; D008075:Lipoproteins, HDL; D002784:Cholesterol
keywords: Apolipoproteins; Atherosclerosis; Lipids; Lipoproteins; Structure