Insights into the client protein release mechanism of the ATP-independent chaperone Spy

Wei He, Xinming Li, Hongjuan Xue, Yuanyuan Yang, Jun Mencius, Ling Bai, Jiayin Zhang, Jianhe Xu, Bin Wu (), Yi Xue () and Shu Quan ()
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Wei He: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Xinming Li: Tsinghua University
Hongjuan Xue: Chinese Academy of Sciences
Yuanyuan Yang: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Jun Mencius: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Ling Bai: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Jiayin Zhang: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Jianhe Xu: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)
Bin Wu: Chinese Academy of Sciences
Yi Xue: Tsinghua University
Shu Quan: East China University of Science and Technology, Shanghai Collaborative Innovation Center for Biomanufacturing (SCICB)

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30499-x

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