He, Wei; Li, Xinming; Xue, Hongjuan; Yang, Yuanyuan; Mencius, Jun; Bai, Ling; Zhang, Jiayin; Xu, Jianhe; Wu, Bin; Xue, Yi; Quan, Shu

NATURE COMMUNICATIONS

2022, 13,

He, Wei; Li, Xinming; Xue, Hongjuan; Yang, Yuanyuan; Mencius, Jun; Bai, Ling; Zhang, Jiayin; Xu, Jianhe; Wu, Bin; Xue, Yi; Quan, Shu

How ATP-independent chaperones release their clients without energy input remains enigmatic. Here the authors discover that chaperone Spy uses its long, disordered N terminus to facilitate client release through competitive, dynamic intramolecular interactions with Spy's client binding surface. Molecular chaperones play a central role in regulating protein homeostasis, and their active forms often contain intrinsically disordered regions (IDRs). However, how IDRs impact chaperone action remains poorly understood. Here, we discover that the disordered N terminus of the prototype chaperone Spy facilitates client release. 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. This intramolecular interaction results in a dynamic competition of the N terminus with the client for binding to Spy, which promotes client discharge. 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.