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A Phosphosignaling Adaptor Primes the AAA+ Protease ClpXP to Drive Cell Cycle-Regulated Proteolysis. | LitMetric
The response regulator CpdR couples phosphorylation events in Caulobacter crescentus with the AAA+ protease ClpXP to provide punctuated degradation of crucial substrates involved in cell cycle regulation. CpdR functions like an adaptor to alter substrate choice by ClpXP; however, it remains unclear how CpdR influences its multiple targets. Here we show that, unlike canonical ClpXP adaptors, CpdR alone does not strongly bind its substrate. Instead, CpdR binds the N-terminal domain of ClpX and prepares (primes) the unfoldase for substrate engagement. This priming creates a recruitment interface that docks multiple substrates and additional adaptor components. We show that adaptor-dependent priming of ClpX avoids concentration-dependent inhibition that limits traditional scaffolding adaptors. Phosphosignaling disrupts the adaptor-protease interaction, and mutations in CpdR that impact ClpX binding tune adaptor activity and biological function. Together, these results reveal how a single adaptor can command global changes in proteome composition through priming of a protease.
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