Decoding chaperone complexes: Insights from NMR spectroscopy

Molecular chaperones play a key role in protein homeostasis by preventing misfolding and aggregation, assisting in proper protein folding, and sometimes even disaggregating formed aggregates. Chaperones achieve this through a range of transient weak protein-protein interactions, which are difficult to study using traditional structural and biophysical techniques. Nuclear magnetic resonance (NMR) spectroscopy, however, is well-suited for studying such dynamic states and interactions. A wide range of NMR experiments have been particularly valuable in understanding the mechanisms of chaperone function, as they can characterize disordered protein structures, detect weak and nonspecific interactions involving sparsely populated states, and probe the conformational dynamics of proteins and their complexes. Recent advances in NMR have significantly enhanced our knowledge of chaperone mechanisms, especially chaperone-client interactions, despite the inherent challenges posed by the flexibility and complexity of these systems. In this review, we highlight contributions of NMR to the chaperone field, focusing on the work carried out in our laboratory, which have provided insights into how chaperones maintain function within the cellular environment and interact with various protein substrates.