Impact of Bilayer Lipid Composition on the Structure and Topology of the Transmembrane Amyloid Precursor C99 Protein

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• 作者：Yuanli Song ; Kathleen F. Mittendorf ; Zhenwei Lu ; Charles R. Sanders
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 19, 2014
• 年：2014
• 卷：136
• 期：11
• 页码：4093-4096
• 全文大小：396K
• 年卷期：v.136,no.11(March 19, 2014)
• ISSN：1520-5126

文摘

C99 (also known as 尾-CTF) is the 99 residue transmembrane C-terminal domain (residues 672鈥?70) of the amyloid precursor protein and is the immediate precursor of the amyloid-尾 (A尾) polypeptides. To test the dependence of the C99 structure on the composition of the host model membranes, NMR studies of C99 were conducted both in anionic lyso-myristoylphosphatidylglycerol (LMPG) micelles and in a series of five zwitterionic bicelle compositions involving phosphatidylcholine and sphingomyelin in which the acyl chain lengths of these lipid components varied from 14 to 24 carbons. Some of these mixtures are reported for the first time in this work and should be of broad utility in membrane protein research. The site-specific backbone ¹⁵N and ¹H chemical shifts for C99 in LMPG and in all five bicelle mixtures were seen to be remarkably similar, indicating little dependence of the backbone structure of C99 on the composition of the host model membrane. However, the length of the transmembrane span was seen to vary in a manner that alters the positioning of the 纬-secretase cleavage sites with respect to the center of the bilayer. This observation may contribute to the known dependency of the A尾42-to-A尾40 production ratio on both membrane thickness and the length of the C99 transmembrane domain.