Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action


Protein folding in the cell relies on the orchestrated action of conserved families of molecular chaperones, the Hsp70 and Hsp90 systems. Hsp70 acts early and Hsp90 late in the folding path, yet the molecular basis of this timing is enigmatic, mainly because the substrate specificity of Hsp90 is poorly understood. Here, we obtained a structural model of Hsp90 in complex with its natural disease-associated substrate, the intrinsically disordered Tau protein. Hsp90 binds to a broad region in Tau that includes the aggregation-prone repeats. Complementarily, a 106-Å-long substrate-binding interface in Hsp90 enables many low-affinity contacts. This allows recognition of scattered hydrophobic residues in late folding intermediates that remain after early burial of the Hsp70 sites. Our model resolves the paradox of how Hsp90 specifically selects for late folding intermediates but also for some intrinsically disordered proteins-through the eyes of Hsp90 they look the same.

DOI: 10.1016/j.cell.2014.01.037

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@article{Karagz2014Hsp90TauCR, title={Hsp90-Tau Complex Reveals Molecular Basis for Specificity in Chaperone Action}, author={G{\"{u}ls{\"{u}n Elif Karag{\"{o}z and Afonso M. S. Duarte and Elias Akoury and Hans Ippel and Jacek Biernat and Tania Mor{\'a}n Luengo and Martina Radli and Tatiana Didenko and Bryce A. Nordhues and Dmitry B. Veprintsev and Chad A Dickey and E . - M . Mandelkow and Markus Zweckstetter and Rolf Boelens and Tobias Madl and Stefan G D R{\"{u}diger}, journal={Cell}, year={2014}, volume={156}, pages={963-974} }