This revealed that both the bacterial and human versions of the Hsp70 chaperone interact only with unfolded proteins. therefore used NMR to investigate which forms of a protein Hsp70 binds to. However, it was not clear whether Hsp70 can also associate with the mature, correctly folded form of the proteins.Ī technique called Nuclear Magnetic Resonance (NMR) spectroscopy can distinguish between mature, unfolded and chaperone-bound forms of the same protein. One, called Hsp70, binds to proteins that are incorrectly folded to help them to mature into their correct structures. There are many different types of chaperones that play different roles inside cells. These protein forms are not able to work effectively and in some cases may even cause diseases.Ĭhaperone proteins help other proteins to fold correctly and are found in living organisms ranging in complexity from bacteria to humans. However, proteins sometimes fold incorrectly or unfold. Newly made proteins need to ‘fold’ into precise three-dimensional shapes in order to carry out their roles. Proteins are the workhorses of a cell and are involved in almost all biological processes. Our measurements establish that both bacterial and human Hsp70 chaperones interact with clients by selecting the unfolded state from a pre-existing array of interconverting structures, suggesting a conserved mode of client recognition among Hsp70s and highlighting the importance of molecular dynamics in this recognition event. We directly quantify the flux along CS and IF pathways using solution NMR spectroscopy that exploits a methyl TROSY effect and selective isotope-labeling methodologies. Here we focus on the ubiquitous and conserved Hsp70 chaperone which oversees the integrity of the cellular proteome through its ATP-dependent interaction with client proteins. In such a process the bound structure can be selected from the ensemble of interconverting ligands a priori (conformational selection, CS) or may form once the ligand is bound (induced fit, IF). Molecular recognition is integral to biological function and frequently involves preferred binding of a molecule to one of several exchanging ligand conformations in solution.
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