Comprehensive mapping of mutations in TDP-43 and α-Synuclein that affect stability and binding

Abstract

Abnormal aggregation and amyloid inclusions of TAR DNA-binding protein 43 (TDP-43) and α-Synuclein (α-Syn) are frequently co-observed in amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. Several reports showed TDP-43 C-terminal domain (CTD) and α-Syn interact with each other and the aggregates of these two proteins colocalized together in different cellular and animal models. Molecular dynamics simulation was conducted to elucidate the stability of the TDP-43 and Syn complex structure. The interfacial mutations in protein complexes changes the stability and binding affinity of the protein that may cause diseases. Here, we have utilized the computational saturation mutagenesis approach including structure-based stability and binding energy calculations to compute the systemic effects of missense mutations of TDP-43 CTD and α-Syn on protein stability and binding affinity. Most of the interfacial mutations of CTD and α-Syn were found to destabilize the protein and reduced the protein binding affinity. The results thus shed light on the functional consequences of missense mutations observed in TDP-43 associated proteinopathies and may provide the mechanisms of co-morbidities involving these two proteins.

Communicated by Ramaswamy H. Sarma

Keywords:

• TDP-43 CTD
• α-Synuclein
• missense mutations
• protein interface
• stability
• binding affinity

Acknowledgements

The authors acknowledge the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, for technical and financial support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

Conceptualization, S.H., B.S.A., and V.K.; methodology, S.H., S.M., B.S.A., A.P., and V.K.; software, S.A., S.H., and H.O.T; formal analysis, S.A., B.S.A, T.A., and S.H; data curation, S.A., S.H., A.P., and V.K.; writing—original draft preparation, S.H., R.M.F., S.A., and A.E.; writing—review and editing, all authors; supervision, S.H., B.S.A., and V.K. All authors contributed to the article and have approved the submitted version.

Consent for publication

All authors consent for the publication of this study.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This project was funded by the Deanship of Scientific Research (DSR) at King Abdulaziz University, Jeddah, under grant no. (G: 765-140-1441). The authors, therefore, acknowledge with thanks DSR for technical and financial support.