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Frustration analysis of TBK1 missense mutations reported in ALS/FTD and cancer patients

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Abstract

Tank-binding kinase 1 (TBK1) is a multifunctional kinase having essential roles in cellular processes, autophagy/mitophagy, and selective clearance of damaged proteins. More than 90 mutations in the TBK1 gene are linked with multiple cancer types, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Some of these missense mutations disrupt the abilities of TBK1 to dimerize, associate with the mitophagy receptor optineurin (OPTN), autoactivate, or catalyze phosphorylation. Some mutations may cause severe dysregulation of the pathway, while others induce a limited disruption. Here, we have studied those mutations reported in cancer, ALS and FTD, and subsequently investigated the effect of missense mutations on the structure and function of TBK1 for localized residual frustration change. Out of 33 ALS/FTD causing mutations and 28 oncogenic mutations, 10 mutations and 12 oncogenic mutations showed significant change in the residual frustration. The local frustration plays an important role in the conformation of protein structure in active and inactive kinases. Our analysis reports the change in residual frustration state, conformational change and effect on active and inactive TBK1 function due to ALS/FTD causing and oncogenic missense mutations.

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Acknowledgements

This work was supported by Taif University Researchers Supporting Project Number (TURSP-2020/131), Taif University, Taif, Saudi Arabia. MIH acknowledges the Council of Scientific and Industrial Research for financial support [Project No. 27(0368)/20/EMR-II]. The authors sincerely thank the Department of Science and Technology, Government of India, for the FIST support (FIST program No. SR/FST/LSII/2020/782).

Funding

This work was supported by Taif University Researchers Supporting Project Number (TURSP-2020/131), Taif University, Taif, Saudi Arabia and the Indian Council of Medical Research (Grant No. ECD/Adhoc/2/2021-22).

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Authors and Affiliations

  1. Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, Uttar Pradesh, 201303, India

    Fatima Khatoon & Vijay Kumar

  2. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia

    Farah Anjum & Alaa Shafie

  3. Department of Biology, College of Science, University of Hail, PO Box 2440, Hail, Saudi Arabia

    Mohd. Adnan

  4. Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, 110025, India

    Md Imtaiyaz Hassan

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  1. Fatima Khatoon
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  2. Vijay Kumar
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  3. Farah Anjum
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  4. Alaa Shafie
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  5. Mohd. Adnan
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Contributions

The authors confirm contribution to the paper as follows: Study conception and design were done by FK, FA, MIH, and VK; data collection and analysis were carried out by FK, AS, and MA; interpretation of results was done by FK; FA and AS, draft manuscript preparation was done by FK, VK, MA, AS, and MIH. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Vijay Kumar or Md Imtaiyaz Hassan.

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Khatoon, F., Kumar, V., Anjum, F. et al. Frustration analysis of TBK1 missense mutations reported in ALS/FTD and cancer patients. 3 Biotech 12, 174 (2022). https://doi.org/10.1007/s13205-022-03240-0

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