Cell-based high-throughput screening identifies IBT21 as a chemical chaperone, that inhibits ER protein aggregation and prevents the cell death caused by a proteotoxin, the aggregation-prone prion protein.
ATP consumption enables chaperones to exploit the different kinetic properties of their conformational states to exhibit a non-equilibrium affinity for their substrates that is orders of magnitude higher than its equilibrium value.
Cells accumulate damaged proteins during aging and, by compromising the function of chaperones in folding newly synthesized G1 cyclins, proteostasis breakdown inhibits cell-cycle entry and drives yeast cells into senescence.
A combined NMR and kinetic study demonstrates how the dynamic transition of a molecular chaperone between different oligomerization states can modulate its activity by altering the binding kinetics and energetics of non-native proteins.
Modeling and biophysics show that the unstructured acidic tail of the Sm protein Hfq mimics nucleic acid to auto inhibit its chaperone activity, preventing Hfq from being sequestered by inauthentic substrates and providing insight into the evolution of Hfq's chaperone function among bacterial genera.