The majority of proteins depend on a well-defined three-dimensional structure to obtain their functionality. In order to prevent misfolding, aggregation, and the generation of toxic species, the process of protein folding in the cell is often guided by molecular chaperones. These complex protein networks either interact with substrate polypeptides to help them fold; unfold misfolded species; resolve aggregates; or deliver substrates to proteolysis. Very little structural information, however, is available about how substrates are bound by chaperones or the manner in which they are protected from misfolding and aggregation. This lack of information arises from the highly dynamic nature of chaperone-substrate complexes – a trait that, fortunately for us, makes them great targets for NMR spectroscopy.
In our lab we are interested in characterizing the molecular interactions and dynamics of these large molecular chaperones with their unfolded/misfolded/aggregated protein targets. In this project we use solution-state NMR to probe molecular interactions between a hundreds-of-kilodalton large chaperone complex and “client” proteins, as well as the structural and dynamic features of these complexes.