Lecture title: Allosteric Control of Hsp70 Protein Folding Activity
Speaker: Wayne A. Hendrickson
Time: 16:00, Nov. 9th, 2023
Venue: Auditorium, ShanghaiTech University 上科大报告厅 （教学中心对面）
Host: Haitao Yang, SIAIS Executive Director
Heat-shock proteins of 70 kDa (Hsp70s) are vital for all of life and notably important for protein folding. Hsp70s use iterations of ATP binding and hydrolysis in one domain to control the binding and release of client polypeptides in a second domain. ATP-fueled cycles of Hsp70 activity promote proper protein folding by blocking or reversing the aggregation of misfolded intermediates, often stress induced. To explain functional characteristics of Hsp70 DnaK and structure-inspired mutants, we developed a theoretical model of allosteric equilibria among Hsp70 conformational states: when in ATP, a restraining state (R) restricts ATP hydrolysis and does not bind client peptides, whereas a stimulating state (S) hydrolyzes ATP rapidly and binds substrates well but with rapid binding kinetics. ATP hydrolysis uncouples the allosteric interactions, and clients are then caught in tight complexes until ejected by ATP rebinding. This model for allosteric regulation is supported by structures in the postulated S state, by biochemical tests and additional mutations, and by in cristallo hydrolysis reactions in the ATP-binding domain.
