Role of Diffusion in Unfolding and Translocation of Multidomain Titin I27 Substrates by a Clp ATPase Nanomachine
Role of Diffusion in Unfolding and Translocation of Multidomain Titin I27 Substrates by a Clp ATPase Nanomachine
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DOI：
10.1021/acs.jpcb.8b10282
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发表时间：
2019-03-28
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：
Jayidialesaadi, Abdolreza;Flournoy, Shanice M.;Stan, George
AAA+纳米机器对多结构域底物蛋白（SP）的降解发生在标记末端的下游。环状ATP酶组分，如ClpY，施加重复的机械力以影响多肽区段通过狭窄的中央通道的结构域解折叠和移位。我们研究这些机制，通过原子Langevin动力学模拟的C-末端标记的SP在变构ClpY周期。我们发现，单体SP是通过单一的解折叠途径和快速的时间尺度，而多聚体SP涉及分支的途径和较慢的时间尺度。这些不同的机制是由于在多域SP的C-末端域的旋转扩散较慢，阻碍了访问软机械方向。在特定于激光光镊实验的几何结构中，涉及受约束的SP N-末端，当沿N-C方向沿着施加拉力时，发现单体和四聚体SP都存在单一的解折叠路径。非天然的相互作用通过削弱C-末端界面来调节未受约束的单体的展开，但对受约束的SP的展开没有显著贡献。在这些结果的基础上，我们提出，限制SP动力学和ATP酶动力学的相互作用的基础分区的多域SP到完全降解的产品和未降解的片段，包括折叠域。
Degradation of multidomain substrate proteins (SPs) by AAA+ nanomachines takes place processively from the tagged terminal. Ring-shaped ATPase components, such as ClpY, apply repetitive mechanical forces to effect domain unfolding and translocation of polypeptide segments through a narrow central channel. We study these mechanisms through atomistic Langevin dynamics simulations of C-terminal-tagged SPs in allosteric ClpY cycles. We find that monomeric SPs are processed through single unfolding pathways and fast timescales, whereas multimeric SPs involve branched pathways and slower timescales. These distinct mechanisms are attributed to the slower rotational diffusion of the C-terminal domain in multidomain SPs that hinders access to the soft mechanical direction. In the geometry specific to laser optical tweezers experiments, involving a restrained SP N-terminal, a single unfolding pathway is found for both monomeric and tetrameric SPs as pulling is applied along the N-C direction. Non-native interactions modulate unfolding of unrestrained monomers by weakening the C-terminal interface but do not contribute significantly to unfolding of restrained SPs. On the basis of these results, we propose that the interplay of restricted SP dynamics and ATPase kinetics underlies partitioning of multidomain SPs into completely degraded products and undegraded fragments comprising folded domains.