Zhang Moxin, Xue Bin, Li Qingtai, Shi Rui, Cao Yi, Wang Wei, Li Jingyuan
Zhejiang Province Key Laboratory of Quantum Technology and Device, School of Physics, Zhejiang University, Hangzhou310058, China.
Collaborative Innovation Center of Advanced Microstructures, National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing210093, China.
JACS Au. 2022 Dec 30;3(1):93-104. doi: 10.1021/jacsau.2c00414. eCollection 2023 Jan 23.
Reversible interaction between intrinsically disordered proteins (IDPs) is considered as the driving force for liquid-liquid phase separation (LLPS), while the detailed description of such a transient interaction process still remains a challenge. And the mechanisms underlying the behavior of IDP interaction, for example, the possible relationship with its inherent conformational fluctuations and sequence features, remain elusive. Here, we use atomistic molecular dynamics (MD) simulation to investigate the reversible association of the LAF-1 RGG domain, the IDP with ultra-low LLPS concentration (0.06 mM). We find that the duration of the association between two RGG domains is highly heterogeneous, and the sustained associations essentially dominate the IDP interaction. More interestingly, such sustained associations are mediated by a finite region, that is, the C-terminal region 138-168 (denoted as a contact-prone region). We noticed that such sequence tendency is attributed to the extended conformation of the RGG domain during its inherent conformational fluctuations. Hence, our results suggest that there is a certain region in this low-complexity IDP which can essentially dominate their interaction and should be also important to the LLPS. And the inherent conformational fluctuations are actually essential for the emergence of such a hot region of IDP interaction. The importance of this hot region to LLPS is verified by experiment.
内在无序蛋白（IDP）之间的可逆相互作用被认为是液-液相分离（LLPS）的驱动力，而对这种瞬态相互作用过程的详细描述仍然是一个挑战。并且IDP相互作用行为背后的机制，例如，与其固有构象波动和序列特征的可能关系，仍然难以捉摸。在这里，我们使用原子分子动力学（MD）模拟来研究LAF-1 RGG结构域的可逆缔合，该IDP具有超低的LLPS浓度（0.06 mM）。我们发现两个RGG结构域之间缔合的持续时间高度异质，并且持续缔合基本上主导了IDP相互作用。更有趣的是，这种持续缔合由一个有限区域介导，即C末端区域138-168（表示为易接触区域）。我们注意到这种序列趋势归因于RGG结构域在其固有构象波动期间的延伸构象。因此，我们的结果表明，在这种低复杂性IDP中存在一个特定区域，它可以基本上主导它们的相互作用，并且对LLPS也应该很重要。并且固有构象波动实际上对于IDP相互作用的这种热点区域的出现至关重要。该热点区域对LLPS的重要性通过实验得到验证。
