Molecular Diversity ( IF 3.9 ) Pub Date : 2022-12-08 , DOI: 10.1007/s11030-022-10579-2
Kavya Pandya 1 , Neeru Singh 1
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Abstract
DNA damage response (DDR) and autophagy are concerned with maintaining cellular homeostasis and dysregulation of these two pathways lead to pathologic conditions including tumorigenesis. Autophagy is activated as a protective mechanism during DDR which is indicative of their functional cooperativity but the molecular mechanism leading to the convergence of these two pathways during genotoxic stress remains elusive. In this study, through in silico analysis, we have shown an interaction between the Mediator of DNA damage checkpoint 1 (MDC1), an important DDR-associated protein, and Beclin-1, an autophagy inducer. MDC1 is an adaptor or scaffold protein known to regulate DDR, apoptosis, and cell cycle progression. While, Beclin-1 is involved in autophagosome nucleation and exhibits affinity for binding to Fork-head-associated domain (FHA) containing proteins. The FHA domain is commonly conserved in DDR-related proteins including MDC1. Through molecular docking, we have predicted the modeled complex between the MDC1 FHA domain and the Beclin-1 Coiled coil domain (CCD). The docking complex was modeled using ClusPro2.0, based on the crystal structure for the dimerized MDC1 FHA domain and Beclin-1 CCD. The complex stability and binding affinities were assessed using a Ramachandran plot, MD simulation, MM/GBSA, and PRODIGY webserver. Finally, the hot-spot residues at the interface were determined using computational alanine scanning by the DrugScorePPI webserver. Our analysis unveils significant interaction between MDC1 and Beclin-1, involving hydrogen bonds, non-bonded contacts, and salt bridges and indicates MDC1 possibly recruits Beclin-1 to the DSBs, as a consequence of which Beclin-1 is able to modulate DDR.
Graphical abstract
中文翻译：
计算机研究揭示了 DDR 的 MDC1 和自噬的 Beclin-1 之间非常规的相互作用
摘要
DNA 损伤反应 (DDR) 和自噬与维持细胞稳态有关，这两种途径的失调会导致包括肿瘤发生在内的病理状况。自噬作为 DDR 期间的保护机制被激活，这表明它们的功能协同性，但在基因毒性应激期间导致这两种途径聚合的分子机制仍然难以捉摸。在这项研究中，通过计算机分析，我们展示了 DNA 损伤检查点介体 1 (MDC1)（一种重要的 DDR 相关蛋白）和 Beclin-1（一种自噬诱导剂）之间的相互作用。MDC1 是一种接头蛋白或支架蛋白，已知可调节 DDR、细胞凋亡和细胞周期进程。同时，Beclin-1 参与自噬体成核，并表现出与含有叉头相关结构域 (FHA) 的蛋白质结合的亲和力。FHA 结构域在 DDR 相关蛋白（包括 MDC1）中通常是保守的。通过分子对接，我们预测了 MDC1 FHA 结构域和 Beclin-1 卷曲线圈结构域 (CCD) 之间的模型复合体。基于二聚化 MDC1 FHA 结构域和 Beclin-1 CCD 的晶体结构，使用 ClusPro2.0 对对接复合物进行建模。使用 Ramachandran 图、MD 模拟、MM/GBSA 和 PRODIGY 网络服务器评估复合物稳定性和结合亲和力。最后，通过 DrugScore PPI网络服务器使用计算丙氨酸扫描确定界面处的热点残基。我们的分析揭示了 MDC1 和 Beclin-1 之间的显着相互作用，包括氢键、非键接触和盐桥，并表明 MDC1 可能将 Beclin-1 招募到 DSB，因此 Beclin-1 能够调节 DDR。
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