Allosteric Modulation of Intact γ-Secretase Structural Dynamics
Allosteric Modulation of Intact γ-Secretase Structural Dynamics
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DOI：
10.1016/j.bpj.2017.10.012
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发表时间：
2017-12-19
影响因子：
3.4
通讯作者：
Bahar, Ivet
中科院分区：
文献类型：
--
作者：
Lee, Ji Young;Feng, Zhiwei;Bahar, Ivet
作为一种蛋白酶复合物，参与淀粉样前体蛋白的裂解，从而形成与阿尔茨海默氏病有关的淀粉样β原纤维，γ-分泌酶是开发阿尔茨海默氏病治疗方法的重要靶点，γ-分泌酶由四个亚基组成：胞外 (EC) 结构域中的尼卡斯特林 (NCT)、早老素-1 (PS1)、前咽缺陷 1 和早老素跨膜 (TM) 结构域中的增强子 2。 NCT 和 PS1 在结合淀粉样β前体蛋白和调节 PS1 催化活性方面发挥着重要作用。然而，底物/调节剂结合与催化活性之间耦合的分子机制仍有待阐明。最近对完整人类伽马分泌酶冷冻电子显微镜结构的测定为详细研究该复合物的结构动力学开辟了道路。我们的分析基于膜耦合各向异性网络模型，揭示了相对于 PS1 的两种类型的 NCT 运动：弯曲和扭曲。这些是盖状 NCT 相对于 PS1 上的亲水环 1 (HL1) 的“打开”和“关闭”状态之间波动的基础，从而允许或阻止底物肽（EC 部分）接近 HL1 和邻近的螺旋 TM2。除了这种交替进入机制之外，PS1 中心腔体积的波动有利于底物裂解的催化位点的暴露。成药性模拟表明，γ-分泌酶呈现出催化活性的正构或变构抑制的几个热点，与实验数据一致。特别是，EC 和 TM 结构域之间界面处的铰链区，靠近 NCT 的叶间沟，作为同种异体靶向位点出现，将影响 HL1/TM2 和催化口袋之间的耦合，据我们所知，为基于结构设计γ-分泌酶蛋白酶活性的新型变构调节剂开辟了新途径。
As a protease complex involved in the cleavage of amyloid precursor proteins that lead to the formation of amyloid beta fibrils implicated in Alzheimer's disease, gamma-secretase is an important target for developing therapeutics against Alzheimer's disease, gamma-secretase is composed of four subunits: nicastrin (NCT) in the extracellular (EC) domain, presenilin-1 (PS1), anterior pharynx defective 1, and presenilin enhancer 2 in the transmembrane (TM) domain. NCT and PS1 play important roles in binding amyloid beta precursor proteins and modulating PS1 catalytic activity. Yet, the molecular mechanisms of coupling between substrate/modulator binding and catalytic activity remain to be elucidated. Recent determination of intact human gamma-secretase cryo-electron microscopy structure has opened the way for a detailed investigation of the structural dynamics of this complex. Our analysis, based on a membrane-coupled anisotropic network model, reveals two types of NCT motions, bending and twisting, with respect to PS1. These underlie the fluctuations between the "open" and "closed" states of the lid-like NCT with respect to a hydrophilic loop 1 (HL1) on PS1, thus allowing or blocking access of the substrate peptide (EC portion) to HL1 and to the neighboring helix TM2. In addition to this alternating access mechanism, fluctuations in the volume of the PS1 central cavity facilitate the exposure of the catalytic site for substrate cleavage. Druggability simulations show that gamma-secretase presents several hot spots for either orthosteric or allosteric inhibition of catalytic activity, consistent with experimental data. In particular, a hinge region at the interface between the EC and TM domains, near the interlobe groove of NCT, emerges as an allo-targeting site that would impact the coupling between HL1/TM2 and the catalytic pocket, opening, to our knowledge, new avenues for structure-based design of novel allosteric modulators of gamma-secretase protease activity.