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

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Tank-binding kinase 1 (TBK1) is crucial for cellular processes, including autophagy and protein clearance.
• Over 90 mutations in the TBK1 gene are associated with cancer, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD).
• Some TBK1 mutations impair its dimerization, autoactivation, and phosphorylation capabilities, leading to pathway dysregulation.

Purpose of the Study:

• To investigate the structural and functional impact of TBK1 missense mutations found in cancer, ALS, and FTD.
• To analyze how these mutations affect localized residual frustration and protein conformation.
• To understand the consequences of mutations on both active and inactive TBK1 functions.

Main Methods:

• Analysis of TBK1 mutations reported in cancer, ALS, and FTD.
• Computational investigation of localized residual frustration changes in TBK1 mutants.
• Assessment of conformational changes and functional effects on active and inactive TBK1.

Main Results:

• Significant changes in residual frustration were observed in 10 ALS/FTD-associated mutations and 12 oncogenic mutations.
• Local frustration is critical for maintaining the conformation of active and inactive kinases.
• The study identified specific changes in residual frustration states and conformational alterations due to disease-associated mutations.

Conclusions:

• Missense mutations in TBK1 can significantly alter its residual frustration, leading to conformational changes.
• These structural alterations impact the function of TBK1 in both its active and inactive states.
• Understanding these mutation-specific effects is vital for comprehending the pathogenesis of TBK1-related diseases.