Location: HSB G-328, 10:30am (unless otherwise noted)
October 08, 2013 - 2013 Lamport Lecture
Lila Gierasch, Ph.D., Distinguished Professor, University of Massachusetts
The 70-kDa heat shock proteins (Hsp70s) comprise one of the most ubiquitously distributed families of allosteric proteins. Hsp70 molecular chaperones participate in chaperone networks essential to cellular homeostasis, and their intimate involvement in both normal and diseased states has led to their emergence as possible therapeutic targets. The many important cellular functions of Hsp70s rely on communication between their N-terminal nucleotide-binding domain (NBD) and their C-terminal substrate-binding domain (SBD), the former made up of an actin-type fold and the latter a β-sandwich of two distorted four-stranded β-sheets followed by a helical lid sub-domain and an unstructured C-terminal segment. We are using an array of biophysical approaches, with heavy reliance on NMR, to understand this intriguing interdomain communication that is so central to Hsp70 action. Compelling data on the E. coli Hsp70, DnaK, support independence of the NBD and SDB in the ADP-bound state, with the SBD having high affinity for substrate (Swain et al., Mol. Cell 26, 27-39 ; Bertelsen et al., PNAS 106, 8471-8476 ). Upon binding of ATP to the NBD, both domains undergo internal rearrangements and dock onto each other to form one contiguous folded structure, recently captured in x-ray crystal structures (Kityk et al., Mol. Cell 48, 863-874 ; Qi et al., NSMB 20, 900 )). Both earlier NMR data (Swain et al., Mol. Cell 26, 27-39 ; Zhuravleva and Gierasch, PNAS 108, 6987-6992 ) and the recent crystal structures show that the conserved hydrophobic interdomain linker is an intimate participant in the SBD/NBD interface of ATP-bound DnaK. Yet understanding the Hsp70 allosteric mechanism requires knowledge about how this conformational change from the ADP- to ATP-bound states is effected. We have recently identified an intermediate state that provides new structural insights and suggests a mechanism for Hsp70 allostery based on thermodynamic coupling between Hsp70 domains and interdomain interactions (Zhuravleva et al., Cell 151, 1296-1307 ). This coupling model, together with our previous analysis of ATP-induced conformational changes in the NBD (Zhuravleva and Gierasch, PNAS 108, 6987 ), also shows how the Hsp70 conformational equilibrium can be controlled by nucleotide, substrate, and co-chaperones, and how different Hsp70s can be tuned by evolution for different functions. [Supported by NIH grant GM027616]
Alt Time: 4 p.m.
Alt Location: D-209