Extended Data Fig. 10: Loop extrusion as a disaggregation principle.

Insertion and translocation of loops promotes efficient disaggregation, because aggregates may display few accessible polypeptide termini at the surface. Translocation by Hsp100s of polypeptides entangled in aggregates generates pulling forces that promote their dissociation, cooperative disruption of larger structures, and extraction. The ability of Hsp100s to switch between translocation modes is relevant to prevent pore jamming when encountering structures that resist immediate disruption. To dissolve such resistive structures and larger aggregates, many translocation actions are probably required, involving multiple Hsp100 hexamers and other chaperones such as Hsp70, acting at different moments in time and at different locations within the aggregate. The random non-processive action of Hsp70s probably inherently requires multiple Hsp70s working together, in a manner that does not generate large pulling forces, while exploiting rapid binding and unbinding. In contrast, the processive nature of ClpB translocation enables fast, deterministic, and forced dissociation, which further limits re-aggregation and degradation when in combination with rapid refolding.