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首页> 外文期刊>EMBO reports >Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2
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Structure of the intracellular domain of the amyloid precursor protein in complex with Fe65-PTB2

机译：淀粉样前体蛋白与Fe65-PTB2复合的胞内结构域结构

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摘要

Cleavage of the amyloid precursor protein (APP) is a crucial event in Alzheimer disease pathogenesis that creates the amyloid-beta peptide (A beta) and liberates the carboxy-terminal APP intracellular domain (AICD) into the cytosol. The interaction of the APP C terminus with the adaptor protein Fe65 mediates APP trafficking and signalling, and is thought to regulate APP processing and A beta generation. We determined the crystal structure of the AICD in complex with the C-terminal phospho-tyrosine-binding (PTB) domain of Fe65. The unique interface involves the NPxY PTB-binding motif and two alpha helices. The amino-terminal helix of the AICD is capped by threonine T-668, an Alzheimer disease-relevant phosphorylation site involved in Fe65-binding regulation. The structure together with mutational studies, isothermal titration calorimetry and nuclear magnetic resonance experiments sets the stage for understanding T-668 phosphorylation-dependent complex regulation at a molecular level. A molecular switch model is proposed.
机译：淀粉样前体蛋白（APP）的切割是阿尔茨海默氏病发病机理中的关键事件，它会形成淀粉样β肽（A beta）并将羧基末端APP细胞内结构域（AICD）释放到细胞质中。 APP C末端与衔接蛋白Fe65的相互作用介导APP的运输和信号传导，并被认为可调节APP的加工和A beta的产生。我们确定了AICD的晶体结构与Fe65的C末端磷酸酪氨酸结合（PTB）结构域复合。独特的界面涉及NPxY PTB结合基序和两个alpha螺旋。 AICD的氨基末端螺旋被苏氨酸T-668封盖，苏氨酸T-668是与Al65heimer疾病相关的磷酸化位点，参与Fe65结合调控。该结构以及突变研究，等温滴定量热法和核磁共振实验为在分子水平上了解T-668磷酸化依赖性复杂调控奠定了基础。提出了一种分子开关模型。

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