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In silico study reveals unconventional interactions between MDC1 of DDR and Beclin-1 of autophagy

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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.

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Acknowledgements

The authors acknowledge the Indian Institute of Advanced Research Gandhinagar for a seed grant to carry out this work. We would like to thank Dr. Ashutosh Srivastava, Assistant Professor, Biological Engineering, Indian Institute of Technology-Gandhinagar (IITGN) for his valuable comments related to the structural analysis of proteins. We also acknowledge Lady Tata Memorial Trust (LTMT) for providing fellowship to Ms. Kavya Pandya. The authors are thankful to the Gujarat Council of Science and Technology (GUJCOST), Dept. of Science and Technology, Gujarat for providing the PARAM SHAVAK supercomputer facility at IAR.

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  1. Department of Biotechnology and Bioengineering, Indian Institute of Advanced Research, Gandhinagar, India

    Kavya Pandya & Neeru Singh

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  1. Kavya Pandya
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NS did the conceptualization of the study. NS and KP designed the study. KP performed the in silico experiments. NS and KP wrote the manuscript. Both the authors have contributed equally in reviewing and editing the manuscript and approve the final manuscript.

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Correspondence to Neeru Singh.

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Pandya, K., Singh, N. In silico study reveals unconventional interactions between MDC1 of DDR and Beclin-1 of autophagy. Mol Divers 27, 2789–2802 (2023). https://doi.org/10.1007/s11030-022-10579-2

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