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Structural Determination of the Lipid-bound Conformation of ApoLp-III

EMSL Project ID


This research proposal is centered on determining the lipid-bound structure of an exchangeable apolipoprotein, insect apolipophorin-III (apoLp-III), using nuclear magnetic resonance (NMR) and molecular biology techniques. This is an important, unsolved biological question since a lipid-bound conformation modulates other biological functions of human apolipoprotein, by serving either as ligands for cell surface receptors or as activators for key enzymes in lipid metabolism. ApoLp-III serves as a good model for human apolipoproteins in elucidating the structural basis of apolipoprotein-lipoprotein interactions. We have solved the NMR structures of two lipid-free full-length apoLp-IIIs, M. sexta apoLp-III (166-residues) and L. migratoria apoLp-III (164-residues), allowing us to propose several new hypotheses pertaining to the recognition and binding of apoLp-III to lipid surfaces. Our central hypothesis in this proposal is that upon lipid-binding, the lipid-free apoLp-III helix-bundle opens at hinges at one end of the molecule, adopting an extended a-helical structure that exposes hydrophobic surfaces for lipid-binding. Previous experimental evidence strongly supports this hypothesis. However, a final confirmation of this hypothesis requires a lipid-bound structure of apoLp-III and currently we do NOT have such a structure available. A structural study of lipid-bound apoLp-III using x-ray crystallography is impossible, since lipid-bound apoLp-III resists crystallization. Thus, our major objective is to determine the NMR structure of lipid-bound apoLp-III. We anticipate that a lipoprotein-associated structure of apoLp-III will provide a biologically active conformation of human apolipoproteins for the binding to the cell surface receptors such as the LDL-receptor, or activating the lipid metabolic enzymes, such as LCAT. New knowledge of these biological processes may lead to new strategies for the therapeutic intervention in atherosclerosis and Alzheimer’s diseases. This proposal was submitted to NSF January 10th, 2002 for funding.

Project Details

Project type
Capability Research
Start Date
End Date


Principal Investigator

Jianjun Wang
Wayne State University

Team Members

So-Young Shin
Wayne State University

Jianglei Chen
Wayne State University

Bin Chen
Wayne State University

Related Publications

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