Backbone Hydrogen Bond Strengths Can Vary Widely in Transmembrane Helices

被引:28
作者
Cao, Zheng [1 ,4 ]
Hutchison, James M. [2 ,3 ]
Sanders, Charles R. [2 ,3 ]
Bowie, James U. [1 ]
机构
[1] Univ Calif Los Angeles, DOE Inst, Inst Mol Biol, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[2] Vanderbilt Univ, Dept Biochem, Nashville, TN 37240 USA
[3] Vanderbilt Univ, Struct Biol Ctr, Nashville, TN 37240 USA
[4] Beijing Abace Biol Co Ltd, Beijing 100176, Peoples R China
关键词
AMYLOID PRECURSOR PROTEIN; DEUTERIUM FRACTIONATION FACTORS; GAMMA-SECRETASE; MEMBRANE-PROTEINS; INTRAMEMBRANE PROTEOLYSIS; CONFORMATIONAL STABILITY; ALZHEIMERS-DISEASE; DRIVE ASSOCIATION; LAMBDA-REPRESSOR; EXCHANGE-RATES;
D O I
10.1021/jacs.7b04819
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Although backbone hydrogen bonds in trans membrane (TM) helices have the potential to be very strong due to the low dielectric and low water environment of the membrane, their strength has never been assessed experimentally. Moreover, variations in hydrogen bond strength might be necessary to facilitate the TM helix breaking and bending that is often needed to satisfy functional imperatives. Here we employed equilibrium hydrogen/deuterium fractionation factors to measure backbone hydrogen bond strengths in the TM helix of the amyloid precursor protein (APP). We find an enormous range of hydrogen bond free energies, with some, weaker than water-water hydrogen bonds and some over 6 kcal/mol stronger than water-water hydrogen bonds. We find that weak hydrogen bonds are at or near preferred gamma-secretase cleavage sites, suggesting that the sequence of APP and possibly other cleaved TM helices may be designed, in part, to make their backbones accessible; for cleavage. The finding that hydrogen bond strengths in a TM helix can vary widely has implications for membrane protein function, dynamics, evolution, and design.
引用
收藏
页码:10742 / 10749
页数:8
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