![]() ![]() It is estimated that 36.7% of the amino acid sequences in chaperones can be classified as “intrinsically disordered regions” (IDRs, i.e., protein regions lacking fixed tertiary structures) 6. To maintain proteostasis, molecular chaperone proteins, which are fundamental to protein quality control systems in cells, exert multiple functions including de novo folding of nascent polypeptides, preventing aggregation of folding intermediates, disassembling protein aggregates, and directing the degradation of off-pathway misfolded proteins 4, 5. Imbalance in protein homeostasis (“proteostasis”) can lead to protein misfolding and aggregation, which is associated with a variety of human diseases such as peripheral amyloidosis, type II diabetes, cancer, cardiovascular diseases, and many neurodegenerative disorders 1, 2, 3. Our results reveal the mechanism by which Spy releases clients independent of energy input, thus enriching the current knowledge on how ATP-independent chaperones release their clients and highlighting the importance of synergy between IDRs and structural domains in regulating protein function. This intramolecular interaction results in a dynamic competition of the N terminus with the client for binding to Spy, which promotes client discharge. ![]() With NMR spectroscopy and molecular dynamics simulations, we find that the N terminus can bind transiently to the client-binding cavity of Spy primarily through electrostatic interactions mediated by the N-terminal D26 residue. Here, we discover that the disordered N terminus of the prototype chaperone Spy facilitates client release. However, how IDRs impact chaperone action remains poorly understood. Molecular chaperones play a central role in regulating protein homeostasis, and their active forms often contain intrinsically disordered regions (IDRs). ![]()
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