Insights into small heat shock protein and substrate structure during chaperone action derived from hydrogen/deuterium exchange and mass spectrometry.

Small heat shock proteins (sHSP) are a remarkably diverse group of molecular chaperones possessing a degree of structural plasticity unparalleled in other protein superfamilies. In the absence of chemical energy input, these stability sensors can sensitively recognize and bind destabilized proteins, even in the absence of gross misfolding. Cellular conditions regulate affinity towards client proteins allowing tightly controlled switching and tuning of sHSP chaperone capacity. Perturbations of this regulation, through chemical modification or mutation, directly lead to a variety of diseased states. This review explores the structural basis of sHSP oligomeric flexibility and the corresponding functional consequences in the context of a model describing sHSP activity with a set of three coupled thermodynamic equilibria. As current research illuminates many novel physiological roles for sHSP outside of their traditional duties as molecular chaperones, such a conceptual framework provides a sound foundation to describe these emerging functions in physiological and pathological processes