Crystal structure of human apolipoprotein A-I: insights into its protective effect against cardiovascular diseases.
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.
Ajees
A Abdul
AA
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.
Anantharamaiah
G M
GM
Mishra
Vinod K
VK
Hussain
M Mahmood
MM
Murthy
H M Krishna
HM
D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000737:chemistry* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy; D003461:Crystallography; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D017433:Protein Structure, Secondary
D016632:Apolipoprotein A-I; D002316:Cardiotonic Agents; D008055:Lipids