Active-State Structures of a Small Heat-Shock Protein Revealed a Molecular Switch for Chaperone Function.

Small heat-shock proteins (sHsps) maintain cellular homeostasis by binding to denatured client proteins to prevent aggregation. Numerous studies indicate that the N-terminal domain (NTD) of sHsps is responsible for binding to client proteins, but the binding mechanism and chaperone activity regulation remain elusive. Here, we report the crystal structures of the wild-type and mutants of an sHsp from Sulfolobus solfataricus representing the inactive and active state of this protein, respectively. All three structures reveal well-defined NTD, but their conformations are remarkably different. The mutant NTDs show disrupted helices presenting a reformed hydrophobic surface compatible with recognizing client proteins. Our functional data show that mutating key hydrophobic residues in this region drastically altered the chaperone activity of this sHsp. These data suggest a new model in which a molecular switch located in NTD facilitates conformational changes for client protein binding.