Co-chaperones containing tetratricopeptide repeat (TPR) domains enable cooperation between Hsp70 and Hsp90 to maintain cellular proteostasis. Although the details of the molecular interactions between some TPR domains and heat shock proteins are known, we describe a novel mechanism by which Tomm34 interacts with and coordinates Hsp70 activities. In contrast to the previously defined Hsp70/Hsp90-organizing protein (Hop), Tomm34 interaction is dependent on the Hsp70 chaperone cycle. Tomm34 binds Hsp70 in a complex process; anchorage of the Hsp70 C terminus by the TPR1 domain is accompanied by additional contacts formed exclusively in the ATP-bound state of Hsp70 resulting in a high affinity entropically driven interaction. Tomm34 induces structural changes in determinants within the Hsp70-lid subdomain and modulates Hsp70/Hsp40-mediated refolding and Hsp40-stimulated Hsp70 ATPase activity. Because Tomm34 recruits Hsp90 through its TPR2 domain, we propose a model in which Tomm34 enables Hsp70/Hsp90 scaffolding and influences the Hsp70 chaperone cycle, providing an additional role for co-chaperones that contain multiple TPR domains in regulating protein homeostasis.

¶Institute of Microbiology The Czech Academy of Sciences Videnska 1083 142 20 Prague Czech Republic; ‖Department of Biochemistry Faculty of Science Charles University Prague Hlavova 8 128 43 Prague Czech Republic;

**Centre for Translational and Chemical Biology Institute of Structural and Molecular Biology University of Edinburgh Max Born Crescent The King's Buildings Edinburgh EH9 3JR United Kingdom

From the ‡Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Zluty Kopec 7 656 53 Brno Czech Republic;

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PDB
2kho, 4jne, 4po2