Mechanism of the Sequential Trajectory of Allosteric Ring Closure in Human Chaperonin TRiC

Eukaryotic chaperonin TRiC assists in the folding of approximately 10% of the cytosolic proteome through an ATP-driven chamber closure cycle, yet the underlying closure mechanism has remained elusive. Here, using cryo-EM and deep learning analyses, we resolve, at near-atomic resolution, the temporal engagement sequence of the eight distinct subunits during human TRiC ring closure triggered by ATP binding. TRiC closes its chamber through the stepwise extension of an apical helical network among subunits around the ring, coordinated with sequential rotations of the equatorial domains. Each subunit responds differently to ATP, rendering the overall motion asymmetric and ordered. This work delineates the complete structural trajectory of allosteric propagation during ATP-binding-induced, rather than hydrolysis-induced, ring closure, and establishes a mechanistic framework linking ATP-driven conformational dynamics to substrate handling.