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Simulation and Computational Study of RING Domain Mutants of BRCA1 and Ube2k in AD/PD Pathophysiology

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Abstract

Lysine-based post-translational modification (PTM) such as acylation, acetylation, deamination, methylation, SUMOylation, and ubiquitination has proven to be a major regulator of gene expression, chromatin structure, protein stability, protein–protein interaction, protein degradation, and cellular localization. However, besides all the PTMs, ubiquitination stands as the second most common PTM after phosphorylation that is involved in the etiology of neurodegenerative diseases (NDDs) namely, Alzheimer’s disease (AD) and Parkinson’s disease (PD). NDDs are characterized by the accumulation of misfolded protein aggregates in the brain that lead to disease-related gene mutation and irregular protein homeostasis. The ubiquitin–proteasome system (UPS) is in charge of degrading these misfolded proteins, which involve an interplay of E1, E2, E3, and deubiquitinase enzymes. Impaired UPS has been commonly observed in NDDs and E3 ligases are the key members of the UPS, thus, dysfunction of the same can accelerate the neurodegeneration process. Therefore, the aim of this study is firstly, to find E3 ligases that are common in both AD and PD through data mining. Secondly, to study the impact of mutation on its structure and function. The study deciphered 74 E3 ligases that were common in both AD and PD. Later, 10 hub genes were calculated of which protein–protein interaction, pathway enrichment, lysine site prediction, domain, and motif analysis were performed. The results predicted BRCA1, PML, and TRIM33 as the top three putative lysine-modified E3 ligases involved in AD and PD pathogenesis. However, based on structural characterization, BRCA1 was taken further to study RING domain mutation that inferred K32Y, K32L, K32C, K45V, K45Y, and K45G as potential mutants that alter the structural and functional ability of BRCA1 to interact with Ube2k, E2-conjugating enzyme. The most probable mutant observed after molecular dynamics simulation of 50 ns is K32L. Therefore, our study concludes BRCA1, a potential E3 ligase common in AD and PD, and RING domain mutation at sites K32 and K45 possibly disturbs its interaction with its E2, Ube2k.

Graphical Abstract

Graphical representation of all the steps involved to study mutation in the RING domain of BRCA1 which is a common E3 ligase observed in Alzheimer’s disease and Parkinson’s disease.

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The authors confirm that the data supporting the findings of this study are available within the article.

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Acknowledgements

We would like to thank the senior management of Delhi Technological University for their constant support and guidance. The authors would like to thank the University Grant Commission, Government of India, for providing junior research fellowship to NR, NTA ref no 201610125084.

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  1. Mehar Sahu and Neetu Rani have contributed equally to this work and also considered joint first author.

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  1. Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Delhi Technological University (Formerly Delhi College of Engineering), Shahbad Daulatpur, Bawana Road, Delhi, 110042, India

    Mehar Sahu, Neetu Rani & Pravir Kumar

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PK: conceptualized, designed, and supervised this work. MS and NR: drafted the manuscript, analyzed, and interpreted the data, and did the artwork. All authors have read and given consent for submission.

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Sahu, M., Rani, N. & Kumar, P. Simulation and Computational Study of RING Domain Mutants of BRCA1 and Ube2k in AD/PD Pathophysiology. Mol Biotechnol 66, 1095–1115 (2024). https://doi.org/10.1007/s12033-023-01006-4

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