# Glutamic Acid at Position 168 Is a Constitutive Activator of Tank Binding Kinase 1 Catalytic Function

## TL;DR

This study shows that a glutamic acid at position 168 in TBK1 boosts its activity, which is important for understanding its role in diseases like ALS.

## Contribution

The study identifies glutamic acid at position 168 as a constitutive activator of TBK1 kinase activity.

## Key findings

- Glutamic acid at position 168 enhances TBK1 catalytic function.
- The negative charge of glutamic acid contributes to TBK1 activation.
- Variants at codon 168 were evaluated to assess their impact on TBK1 activity.

## Abstract

TANK binding kinase 1 (TBK1) is serine/threonine protein kinase member of the inhibitor of nuclear factor-kB kinase family, with links to the etiology of familial as well as idiopathic Amyotrophic Lateral Sclerosis. It contributes to several regulatory cellular processes such as autophagy, inflammation and apoptosis. Reduction or loss of TBK1 kinase activity is associated with increased risk of ALS, and so understanding the molecular basis of this activity is an important research priority. In this current study, the role of the E168 residue, located adjacent to the active site of TBK1, has been assessed using a combination of artificial and naturally occurring variants found at this codon – evaluated using multiple readouts for TBK1 kinase activity. The results suggest that the negative charge resulting from the presence of a glutamic acid at this codon is a constitutive activator of TBK1 activity.

The online version contains supplementary material available at 10.1007/s12017-025-08894-6.