Asymmetric Conformational Transitions in AAA plus Biological Nanomachines Modulate Direction-Dependent Substrate Protein Unfolding Mechanisms
Asymmetric Conformational Transitions in AAA plus Biological Nanomachines Modulate Direction-Dependent Substrate Protein Unfolding Mechanisms
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DOI：
10.1021/acs.jpcb.7b05963
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发表时间：
2017-07-27
影响因子：
3.3
通讯作者：
Stan, George
中科院分区：
文献类型：
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作者：
Javidialesaadi, Abdolreza;Stan, George
强大的AAA+生物纳米机器，如C1pY，形成六聚环结构，通过展开并穿过狭窄的中央通道，选择性地处理目标降解的异常蛋白质。这一过程的分子细节尚未完全了解。我们进行Langevin动力学模拟使用粗粒度模型的底物蛋白质（SP），Titin 127和它的V13 P变体，线程通过ClpY孔。我们探讨了ClpY表面的异质性和孔宽度的变化对SP取向和SP展开过程中施加的力的方向的影响。我们对比SP展开在一个受约束的几何结构，在单分子力谱实验，并在一个不受约束的几何结构，在体内降解过程中的机制。在开孔构型中，未受约束的SP的展开经由解链机制发生，该解链机制涉及沿沿着弱机械方向施加力。在部分封闭的孔隙中，通过剪切机制，沿沿着强机械方向施加力，发生展开。相比之下，由于沿着强机械方向施加力，受约束件127的展开被限制为剪切机构。我们提出，Clp纳米机器可塑性的基础方向依赖性拉动机制，使通用SP重塑行动。
Powerful AAA+ biological nanomachines, such as C1pY, form hexameric ring structures, which selectively process abnormal proteins targeted for degradation by unfolding and threading them through a narrow central channel. The molecular details of this process are not yet fully understood. We perform Langevin dynamics simulations using a coarse-grained model of substrate proteins (SPs), Titin 127 and its V13P variant, threading through the ClpY pore. We probe the effect of ClpY surface heterogeneity and changes in pore width on SP orientation and the direction of applied force during SP unfolding. We contrast mechanisms of SP unfolding in a restrained geometry, as in single-molecule force spectroscopy experiments, and in an unrestrained geometry, as in the in vivo degradation process. In open pore configurations, unfolding of unrestrained SPs occurs via an unzipping mechanism, which involves force application along a weak mechanical direction. In the partially closed pore, unfolding occurs via a shearing mechanism, with force application along a strong mechanical direction. By contrast, unfolding of the restrained 127 is limited to a shearing mechanism due to application of force along the strong mechanical direction. We propose that Clp nanomachine plasticity underlies direction-dependent pulling mechanisms that enable versatile SP remodeling actions.