淀粉样前体蛋白具有柔性跨膜结构域，并与胆固醇结合。
The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol.
机构信息
Department of Biochemistry, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 USA.
出版信息
Science. 2012 Jun 1;336(6085):1168-71. doi: 10.1126/science.1219988.
Abstract
C99 is the transmembrane carboxyl-terminal domain of the amyloid precursor protein that is cleaved by γ-secretase to release the amyloid-β 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 α helix, making it well suited for processive cleavage by γ-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.
摘要
C99 是淀粉样前体蛋白的跨膜羧基末端结构域，可被 γ-分泌酶切割，释放出与阿尔茨海默病相关的淀粉样-β 多肽。核磁共振和电子顺磁共振波谱显示，C99 的细胞外氨基末端包含一个表面嵌入的“N-螺旋”，随后是一个短的“N-环”连接到跨膜结构域（TMD）。TMD 是一个灵活弯曲的α螺旋，非常适合 γ-分泌酶的连续切割。C99 的滴定显示出胆固醇的结合位点，为胆固醇促进淀粉样蛋白形成的机制提供了深入的了解。在寡聚化中具有既定作用的膜埋 GXXXG 基序（G，甘氨酸；X，任何氨基酸）也被证明在胆固醇结合中起关键作用。C99 的结构和胆固醇结合特性可能有助于阿尔茨海默病治疗药物的设计。
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