当前位置: X-MOL 学术ACS Chem. Neurosci. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Membrane Dynamics of γ-Secretase Provides a Molecular Basis for β-Amyloid Binding and Processing
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2017-08-25 00:00:00 , DOI: 10.1021/acschemneuro.7b00208
Arun Kumar Somavarapu 1 , Kasper P. Kepp 1
Affiliation  

γ-Secretase produces β-amyloid (Aβ) within its presenilin (PS1) subunit, mutations in which cause Alzheimer’s disease, and current therapies thus seek to modulate its activity. While the general structure is known from recent electron microscopy studies, direct loop and membrane interactions and explicit dynamics relevant to substrate processing remain unknown. We report a modeled structure utilizing the optimal multitemplate information available, including loops and missing side chains, account of maturation cleavage, and explicit all-atom molecular dynamics in the membrane. We observe three distinct conformations of γ-secretase (open, semiopen, and closed) that remarkably differ by tilting of helices 2 and 3 of PS1, directly controlling active site availability. The large hydrophilic loop of PS1 where maturation occurs reveals a new helix segment that parallels the likely helix character of other substrates. The semiopen conformation consistently shows the best fit of Aβ peptides, that is, longer residence before release and by inference more trimming. In contrast, the closed, hydrophobic conformation is largely inactive and the open conformation is active but provides fewer optimal interactions and induces shorter residence time and by inference releases Aβ peptides of longer lengths. Our simulations thus provide a molecular basis for substrate processing and changes in the Aβ42/Aβ40 ratio. Accordingly, selective binding to protect the semiopen “innocent” conformation provides a molecular recipe for effective γ-secretase modulators; we provide the full atomic structures for these states that may play a key role in developing selective γ-secretase modulators for treatment of Alzheimer’s disease.

中文翻译:

γ-分泌酶的膜动力学为β-淀粉样蛋白的结合和加工提供了分子基础

γ-分泌酶在早老素(PS1)亚基内产生β-淀粉样蛋白(Aβ),这种突变会引起阿尔茨海默氏病,因此目前的治疗方法试图调节其活性。虽然从最近的电子显微镜研究中已经知道了一般结构,但是与底物处理有关的直接环和膜相互作用以及显式动力学仍然未知。我们报告了利用可用的最佳多模板信息的模型化结构,包括环和缺失的侧链,成熟裂解的说明以及膜中明确的全原子分子动力学。我们观察到了三种不同的γ-分泌酶构象(开放,半开放和封闭),它们通过倾斜PS1的两个螺旋2和3显着不同,从而直接控制了活性位点的可用性。PS1发生熟化的较大亲水环揭示了一个新的螺旋链段,该链段与其他底物的可能的螺旋结构相似。半开放构象始终显示出Aβ肽的最佳适应性,即释放前的停留时间更长,并且可以推断出更多的修饰。相反,封闭的疏水构象在很大程度上是无活性的,而开放的构象是有活性的,但是提供较少的最佳相互作用并诱导较短的停留时间,并且通过推断释放较长长度的Aβ肽。因此,我们的模拟为底物处理和Aβ的变化提供了分子基础。封闭的疏水构象在很大程度上没有活性,而开放的构象在有活性,但是提供的最佳相互作用较少,并且诱导了较短的停留时间,并且通过推理释放了较长长度的Aβ肽。因此,我们的模拟为底物处理和Aβ的变化提供了分子基础。封闭的疏水构象在很大程度上没有活性,而开放的构象在有活性,但是提供的最佳相互作用较少,并且诱导了较短的停留时间,并且通过推理释放了较长长度的Aβ肽。因此,我们的模拟为底物处理和Aβ的变化提供了分子基础。42 / Aβ40的比率。因此,选择性结合以保护半开放的“无辜”构象为有效的γ-分泌酶调节剂提供了分子配方。我们提供了这些状态的完整原子结构,这些结构可能在开发用于治疗阿尔茨海默氏病的选择性γ-分泌酶调节剂中起关键作用。
更新日期:2017-09-15
down
wechat
bug