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Quaternary dynamics and plasticity underlie small heat shock protein chaperone function |
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| Authors: | Florian Stengel Andrew J. Baldwin Alexander J. Painter Nomalie Jaya Eman Basha Lewis E. Kay Elizabeth Vierling Carol V. Robinson Justin L. P. Benesch |
| Affiliation: | aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, and Physical and Theoretical Chemistry Laboratory, South Parks Road, Oxford, OX1 3QZ United Kingdom; ;bDepartments of Molecular Genetics, Biochemistry, and Chemistry, University of Toronto, Toronto, ON, M5S 1A8, Canada; and ;cDepartment of Chemistry & Biochemistry, University of Arizona, Tucson, AZ, 85721 |
| Abstract: | Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network. |
| Keywords: | heterogeneity mass spectrometry polydispersity protein dynamics proteostasis |