Small heat shock proteins in protein aggregation and disaggregation

Many factors leading to unfolding and misfolding of proteins eventually result in protein aggregation. Stress imposed by high temperature was one of the first aggregation-inducing factors studied, and remains one of the main models in this field. The cell needs chaperone proteins to control and counteract the aggregation process. Elimination of aggregates can be achieved by solubilization of aggregates and either refolding of the liberated polypeptides or their proteolysis. Here we focus on the molecular mechanisms by which small Hsps chaperones and chaperones from Hsp100 family in cooperation with Hsp70 and Hsp40 chaperones liberate and refold polypeptides trapped in protein aggregates. It has been proposed that small Hsps associate with aggregating polypeptides, thus changing their biochemical properties so that the subsequent Hsp100-Hsp70 disaggregation process becomes much more efficient. Two members of the small Hsp family, IbpA and IbpB, are present in Escherichia coli. Their cooperation is crucial for prevention of irreversible aggregation of proteins. We investigated the mechanisms by which these chaperones influence the aggregation process. We concentrated on the importance of the Nand C-terminal regions of IbpA for self-oligomerization and chaperone functions. Our results show that the defect in chaperone function, observed in truncated versions of IbpA, is due to the inability of these proteins to interact with substrate proteins and consequently to change the properties of aggregates. The subsequent step in disaggregation and reactivation of polypeptides trapped in aggregates depends on the activities of ATP-dependent Hsp100-Hsp70 chaperones. This process requires the substrate threading through the central channel of hexameric Hsp100 chaperone. At that point the small heat shock proteins start to play an inhibitory role in the process. Our results suggests that Hsp70 chaperone system is responsible for the release of small heat shock proteins at the initial step of disaggregation reaction. L16.2