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\begin{document}

\title{Phosphorylation Mechanism Switching in Histidine Kinases is a Tool for
Fast Protein Evolution: Insights from AlphaFold Models}



\author[1]{Federico Olivieri}%
\author[1]{Marcelo Marti}%
\author[1]{Diana E. Wetzler}%
\affil[1]{Universidad de Buenos Aires Facultad de Ciencias Exactas y Naturales}%


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  \date{June 16, 2024}


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\begin{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.%
\end{abstract}%



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