[No authors listed]
The ClpXP protease plays important roles in protein homeostasis and quality control. ClpX is a ring-shaped AAA+ homohexamer that unfolds target proteins and translocates them into the ClpP peptidase for degradation. AAA+ modules in each ClpX subunit-consisting of a large AAA+ domain, a short hinge-linker element, and a small AAA+ domain-mediate the mechanical activities of the ring hexamer. Here, we investigate the roles of these hinge-linker elements in ClpX function. Deleting one hinge-linker element in a single-chain ClpX pseudohexamer dramatically decreases unfolding and degradation activity, in part by compromising the formation of closed rings, protein-substrate binding, and ClpP binding. Covalently reclosing the broken hinge-linker interface rescues activity. Deleting one hinge-linker element from a single-chain dimer or trimer prevents assembly of stable hexamers. Mutationally disrupting a hinge-linker element preserves closed-ring assembly but reduces ATP-hydrolysis cooperativity and degradation activity. These results indicate that hinge-linker length and flexibility are optimized for efficient substrate unfolding and support a model in which the hinge-linker elements of ClpX facilitate efficient degradation both by maintaining proper ring geometry and facilitating subunit-subunit communication. This model informs our understanding of ClpX as well as the larger AAA+ family of motor proteins, which play diverse roles in converting chemical into mechanical energy in all cells.
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