Initial Substrate Binding of γ-Secretase: The Role of Substrate Flexibility

Shu Li, Wan Zhang, Wei Han

研究成果: Article同行評審

20 引文 斯高帕斯(Scopus)

摘要

γ-Secretase cleaves transmembrane domains (TMD) of amyloid precursor protein (APP), producing pathologically relevant amyloid-β proteins. Initial substrate binding represents a key step of the γ-secretase cleavage whose mechanism remains elusive. Through long time scale coarse-grained and atomic simulations, we have found that the APP TMD can bind to the catalytic subunit presenilin 1 (PS1) on an extended surface covering PS1's TMD2/6/9 and PAL motif that are all known to be essential for enzymatic activity. This initial substrate binding could lead to reduction in the vertical gap between APP's ϵ-cleavage sites and γ-secretase's active center, enhanced flexibility and hydration levels around the ϵ-sites, and the presentation of these sites to the enzyme. There are heterogeneous substrate binding poses in which the substrate is found to bind to either the N- or C-terminal parts of PS1, or both. Moreover, we also find that the stability of the binding poses can be modulated by the flexibility of substrate TMD. Especially, the APP substrate, when deprived of bending fluctuation, does not bind to TMD9 at PS1's C-terminus. Our simulations have revealed further that another substrate of γ-secretase, namely, notch receptors, though bearing a rigid TMD, can still bind to PS1 TMD9, but by a different mechanism, suggesting that the influence of substrate flexibility is context-dependent. Together, these findings shed light on the mechanism of initial substrate docking of γ-secretase and the role of substrate flexibility in this process.

原文English
頁(從 - 到)1279-1290
頁數12
期刊ACS Chemical Neuroscience
8
發行號6
DOIs
出版狀態Published - 21 6月 2017
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