Unravelling The Mechanics Of A Molecular Chaperone

The large molecular chaperone, heat shock protein 90 (Hsp90), is a dimeric ATP-driven molecular machine. It is one of the most abundant proteins found in eukaryotic cells, and is known to function together in complexes with many different co-chaperones. These complexes are involved, amongst other things, in the regulation of cell division and signalling [1]. As such, Hsp90 has emerged as an important target for the development of cancer therapeutics [2]. The exact mechanisms by which Hsp90 undergoes conformational changes, the roles of nucleotides, different domain orientations and how these influence the function of the chaperone in complex with its co-chaperones are mostly unknown. Using a custom-built single molecule optical trapping experimental setup, we have so far elucidated the mechanism by which this large protein folds [3], characterised the role of its flexible charged linker region [4] and performed a detailed comparison of Hsp90 orthologs [5]. Current research efforts are building on these findings to characterise the dimerization of Hsp90, and to study the effect of nucleotide binding and co-chaperones on the conformational cycle and single molecule mechanics of Hsp90. [1] A. J. McClellan, et al. Cell 131, 121-135, (2007). [2] J. S. Isaacs, et al. Cancer cell 3, 213-217, (2003). [3] M. Jahn, et al. Proc. Nat. Acad. Sci. 113, 1232-1237, (2016). [4] M. Jahn, et al. Proc. Nat. Acad. Sci. 111, 17881-17886, (2014). [5] M. Jahn and K. Tych, et al. Structure (under revision) (2017).