Crystal structure of human apolipoprotein A-I: Insights into its protective effect against cardiovascular diseases

A. Abdul Ajees, G. M. Anantharamaiah, Vinod K. Mishra, M. Mahmood Hussain, H. M.Krishna Murthy

Research output: Contribution to journalArticle

189 Citations (Scopus)

Abstract

Despite three decades of extensive studies on human apolipoprotein A-I (apoA-I), the major protein component in high-density lipoproteins, the molecular basis for its antiatherogenic function is elusive, in part because of lack of a structure of the full-length protein. We describe here the crystal structure of lipid-free apoA-I at 2.4 Å. The structure shows that apoA-1 is comprised of an N-terminal four-helix bundle and two C-terminal helices. The N-terminal domain plays a prominent role in maintaining its lipid-free conformation, indicating that mutants with truncations in this region form inadequate models for explaining functional properties of apoA-I. A model for transformation of the lipid-free conformation to the high-density lipoprotein-bound form follows from an analysis of solvent-accessible hydrophobic patches on the surface of the structure and their proximity to the hydrophobic core of the four-helix bundle. The crystal structure of human apoA-I displays a hitherto-unobserved array of positively and negatively charged areas on the surface. Positioning of the charged surface patches relative to hydrophobic regions near the C terminus of the protein offers insights into its interaction with cell-surface components of the reverse cholesterol transport pathway and anti-atherogenic properties of this protein. This structure provides a much-needed structural template for exploration of molecular mechanisms by which human apoA-1 ameliorates atherosclerosis and inflammatory diseases.

Original languageEnglish
Pages (from-to)2126-2131
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number7
DOIs
Publication statusPublished - 14-02-2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

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