Conservation of Apolipoprotein A-I鈥檚 Central Domain Structural Elements upon Lipid Association on Different High-Density Lipoprotein Subclasses

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• 作者：Michael N. Oda ; Madhu S. Budamagunta ; Ethan G. Geier ; Sajiv H. Chandradas ; Baohai Shao ; Jay W. Heinecke ; John C. Voss ; Giorgio Cavigiolio
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：October 1, 2013
• 年：2013
• 卷：52
• 期：39
• 页码：6766-6778
• 全文大小：669K
• 年卷期：v.52,no.39(October 1, 2013)
• ISSN：1520-4995

文摘

The antiatherogenic properties of apolipoprotein A-I (apoA-I) are derived, in part, from lipidation-state-dependent structural elements that manifest at different stages of apoA-I鈥檚 progression from lipid-free protein to spherical high-density lipoprotein (HDL). Previously, we reported the structure of apoA-I鈥檚 N-terminus on reconstituted HDLs (rHDLs) of different sizes. We have now investigated at the single-residue level the conformational adaptations of three regions in the central domain of apoA-I (residues 119鈥?24, 139鈥?44, and 164鈥?70) upon apoA-I lipid binding and HDL formation. An important function associated with these residues of apoA-I is the activation of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for catalyzing HDL maturation. Structural examination was performed by site-directed tryptophan fluorescence and spin-label electron paramagnetic resonance spectroscopies for both the lipid-free protein and rHDL particles 7.8, 8.4, and 9.6 nm in diameter. The two methods provide complementary information about residue side chain mobility and molecular accessibility, as well as the polarity of the local environment at the targeted positions. The modulation of these biophysical parameters yielded new insight into the importance of structural elements in the central domain of apoA-I. In particular, we determined that the loosely lipid-associated structure of residues 134鈥?45 is conserved in all rHDL particles. Truncation of this region completely abolished LCAT activation but did not significantly affect rHDL size, reaffirming the important role of this structural element in HDL function.