Non-destructive dissagregation of protein aggregates is a formidable task mediated by the specialized AAA+ chaperone Hsp104/ClpB in combination with the Hsp70/DnaK chaperone system. The exact mechanism of how the hexameric Hsp104/ClpB proteins perform the task of protein disaggregation or remodeling is largely unknown. The process is ATP-dependent and tight coupling between the ATPase domains within the hexameric ring-complex could be observed. While substrate translocation through the central pore of the ring-shaped hexamer appears to be a central mechanism shared with other AAA+ proteins, a middle domain unique to Hsp104/ClpB could be involved in specific features of the Hsp/ClpB mechanism and its regulation. Recent findings underline the dynamic properties of the molecular complex and might provide a basis to understand substrate interaction, regulation of disaggregation activity, and interactions with co-chaperones.
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