Phosphorylation-induced changes in the energetic frustration in human Tank binding kinase 1

Area of Science:

• Molecular Biology
• Structural Biology
• Biophysics

Background:

• Tank binding kinase 1 (TBK-1) is crucial for immunity, inflammation, autophagy, and cell growth.
• The precise molecular and structural mechanisms of TBK-1 phosphorylation and activation remain largely uncharacterized.

Purpose of the Study:

• To investigate the energy landscape of phosphorylated (active) and unphosphorylated (inactive) human TBK-1.
• To elucidate the interplay between phosphorylation and local frustration in TBK-1 activation.

Main Methods:

• Utilized an algorithm with an energy function implemented in the Frustratometer web server.
• Quantified the role of frustration in TBK-1 activation.
• Analyzed conformational changes, frustration, flexibility, and interatomic motions in different TBK-1 forms.

Main Results:

• Observed significant conformational changes, altered frustration, flexibility, and interatomic motions upon TBK-1 phosphorylation.
• Identified a rigid kinase domain as a minimally frustrated core and frustrated clusters in the C-lobe facilitating activation.
• Found a frustrated interaction network in the SDD domain involved in protein-protein interactions and dimerization.

Conclusions:

• Phosphorylation induces subtle changes in long-range contacts, leading to significant conformational alterations in TBK-1.
• Local frustration plays a critical role in regulating TBK-1's conformational dynamics and activation.
• The study provides key insights into the structural basis of TBK-1 regulation.