The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol

被引：405

作者：

Barrett, Paul J. ^{[1
,2
]}

Song, Yuanli ^{[1
,2
]}

Van Horn, Wade D. ^{[1
,2
]}

Hustedt, Eric J. ^{[3
]}

Schafer, Johanna M. ^{[1
,2
]}

Hadziselimovic, Arina ^{[1
,2
]}

Beel, Andrew J. ^{[1
,2
]}

Sanders, Charles R. ^{[1
,2
]}

机构：

[1] Vanderbilt Univ, Sch Med, Dept Biochem, Struct Biol Ctr, Nashville, TN 37232 USA

[2] Vanderbilt Univ, Sch Med, Inst Biol Chem, Nashville, TN 37232 USA

[3] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

来源：

SCIENCE | 2012年 / 336卷 / 6085期

关键词：

C-TERMINAL DOMAIN; GAMMA-SECRETASE; DIMER; APP; SEQUENCE; MODEL;

D O I：

10.1126/science.1219988

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by gamma-secretase to release the amyloid-beta polypeptides, which are associated with Alzheimer's disease. Nuclear magnetic resonance and electron paramagnetic resonance spectroscopy show that the extracellular amino terminus of C99 includes a surface-embedded "N-helix" followed by a short "N-loop" connecting to the transmembrane domain (TMD). The TMD is a flexibly curved alpha helix, making it well suited for processive cleavage by gamma-secretase. Titration of C99 reveals a binding site for cholesterol, providing mechanistic insight into how cholesterol promotes amyloidogenesis. Membrane-buried GXXXG motifs (G, Gly; X, any amino acid), which have an established role in oligomerization, were also shown to play a key role in cholesterol binding. The structure and cholesterol binding properties of C99 may aid in the design of Alzheimer's therapeutics.

引用

页码：1168 / 1171

页数：4

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