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

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.

Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03240-0.