| 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 A. The structure shows that apoA-I 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 antiatherogenic properties of this protein. This structure provides a much-needed structural template for exploration of molecular mechanisms by which human apoA-I ameliorates atherosclerosis and inflammatory diseases. |
| Authors | A Abdul Ajees, G M Anantharamaiah, Vinod K Mishra, M Mahmood Hussain, H M Krishna Murthy
(Affiliation: Center for Biophysical Sciences and Engineering and Atherosclerosis Research Unit and Department of Medicine, University of Alabama, 1530 3rd Avenue South, Birmingham, AL 35294, USA.)
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| Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 7
Pg. 2126-31
(Feb 14 2006)
ISSN: 0027-8424 United States |
| PMID | 16452169
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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| Chemical References |
- Apolipoprotein A-I
- Cardiotonic Agents
- Lipids
|
| Topics |
- Apolipoprotein A-I
(chemistry, therapeutic use)
- Cardiotonic Agents
(chemistry, therapeutic use)
- Cardiovascular Diseases
(drug therapy)
- Crystallography
- Humans
- Hydrophobicity
- Lipids
(chemistry)
- Protein Structure, Secondary
|
