Structural Studies of Lipid-free Apolipoprotein A-I
EMSL Project ID
7790a
Abstract
Cholesterol is a lipid that is necessary for our body. Only the cholesterol that is in excess in the peripheral cells and blood vessels are the bad cholesterol and need to be transport by the HDL particles to the liver for clearance. The reverse cholesterol transport pathway or the HDL pathway is the major drug target for several major human diseases, including heart disease, diabetes and Alzheimer?s disease. Apolipoprotein A-I (apoAI) is a 243-residue exchangeable apolipoprotein which is the most abundant protein component in HDL (~70%). Depending on the extent of lipidation, apoAI displays a dramatic conformational plasticity and may adopt one of four distinct conformations, including: (1). Lipid-free apoAI conformation (for specific phospholipid-binding). (2). ApoAI on preb-HDL (for specific cholesterol-binding). (3). ApoAI on discoidal HDL (for specific LCAT activation). (4). ApoAI on spherical HDL (for specific HDL-receptor binding). The conformational plasticity indeed enables apoAI to display multiple functions which regulate/direct HDL formation, maturation, transport and metabolism. ApoAI structures at different stages will be critical for our understanding of how HDL is formed, to become mature and then transported into the liver. This knowledge is indeed necessary in designing drugs that target the clearance of the bad cholesterol. This proposal is aimed at solving one of the apoAI conformations, the lipid-free apoAI conformation.
Project Details
Project type
Capability Research
Start Date
2005-04-15
End Date
2006-04-03
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
A complete NMR spectral assignment of the lipid-free mouse apolipoprotein A-I (apoAI) C-terminal truncation mutant, apoAI(1-216) Biomol NMR Assign (2007) 1:109–111 DOI 10.1007/s12104-007-9031-2
Chen B, X Ren, T Neville, WG Jerome, DW Hoyt, DL Sparks, G Ren, and J Wang. 2009. "Apolipoprotein AI tertiary structures determine stability and phospholipid-binding activity of discoidal high-density lipoprotein particles of different sizes." Protein Science 18(5):921-935. doi:10.1002/pro.101