The 鈥渂eta-clasp鈥?model of apolipoprotein A-I 鈥?A lipid-free solution structure determined by electron paramagnetic resonance spectroscopy

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• 作者：Jens O. Lagerstedt^a ; Madhu S. Budamagunta^c ; Grace S. Liu^b ; Nicole C. DeValle^b ; John C. Voss^c ; Michael N. Oda^b ; ^{moda@chori.org}
• 关键词：Apolipoprotein A-I ; High density lipoprotein ; Reverse cholesterol transport ; ABCA1
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：March, 2012
• 卷：1821
• 期：3
• 页码：448-455
• 文件大小：1025 K

摘要

Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and plays a central role in cholesterol metabolism. The lipid-free/lipid-poor form of apoA-I is the preferred substrate for the ATP-binding cassette transporter A1 (ABCA1). The interaction of apoA-I with ABCA1 leads to the formation of cholesterol laden high density lipoprotein (HDL) particles, a key step in reverse cholesterol transport and the maintenance of cholesterol homeostasis. Knowledge of the structure of lipid-free apoA-I is essential to understanding its critical interaction with ABCA1 and the molecular mechanisms underlying HDL biogenesis. We therefore examined the structure of lipid-free apoA-I by electron paramagnetic resonance spectroscopy (EPR). Through site directed spin label EPR, we mapped the secondary structure of apoA-I and identified sites of spin coupling as residues 26, 44, 64, 167, 217 and 226. We capitalize on the fact that lipid-free apoA-I self-associates in an anti-parallel manner in solution. We employed these sites of spin coupling to define the central plane in the dimeric apoA-I complex. Applying both the constraints of dipolar coupling with the EPR-derived pattern of solvent accessibility, we assembled the secondary structure into a tertiary context, providing a solution structure for lipid-free apoA-I. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).