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Phosphorylation Mechanism Switching in Histidine Kinases is a Tool for Fast Protein Evolution: Insights from AlphaFold Models
  • Diana E. Wetzler,
  • Federico Olivieri,
  • Marcelo Marti
Diana E. Wetzler
Universidad de Buenos Aires Facultad de Ciencias Exactas y Naturales

Corresponding Author:[email protected]

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Federico Olivieri
Universidad de Buenos Aires Facultad de Ciencias Exactas y Naturales
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Marcelo Marti
Universidad de Buenos Aires Facultad de Ciencias Exactas y Naturales
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Abstract

Histidine kinases (HKs) are a central part of bacterial environmental-sensing two component systems, providing their hosts with the ability to respond to a wide range of physical and chemical signals, being a paradigmatic example of protein diversity and molecular evolution. HK are multidomain proteins consisting of at least a sensor domain, dimerization and phosphorylation domain (DHp) and a catalytic domain. They work as homodimers, and the existence of two different autophosphorylation mechanisms (cis and trans), has been proposed as relevant for pathway specificity. Although several HKs have been intensively studied, a precise sequence-to-structure explanation of why and how either cis or trans phosphorylation occurs, is still unavailable, nor is there any evolutionary analysis on the subject. In this work we show that AlphaFold can accurately determine whether a HK dimerizes in a cis or trans structure. We then use it to explore the molecular determinants of the phosphorylation mechanism. We conclude that it is the difference in lengths of the helices surrounding the DHp loop that determines the mechanism. We also show that very small changes in these helices can cause a mechanism switch, providing these systems with a way to diverge rapidly and adapt to new stimuli.
Submitted to PROTEINS: Structure, Function, and Bioinformatics
16 Feb 2024Review(s) Completed, Editorial Evaluation Pending
28 Feb 2024Editorial Decision: Revise Major
09 Apr 2024Assigned to Editor
09 Apr 2024Submission Checks Completed
09 Apr 2024Reviewer(s) Assigned