title: Novel Entropically Driven Conformation-specific Interactions with Tomm34 Protein Modulate Hsp70 Protein Folding and ATPase Activities.
abstract: 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.
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic;
authors.forename: Michal
authors.initials: M
authors.lastname: Durech
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic;
authors.forename: Filip
authors.initials: F
authors.lastname: Trcka
authors.affiliation: ¶Institute of Microbiology, The Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic; ‖Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Prague, Czech Republic;
authors.forename: Petr
authors.initials: P
authors.lastname: Man
authors.affiliation: **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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Blackburn
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic;
authors.forename: Lenka
authors.initials: L
authors.lastname: Hernychova
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic;
authors.forename: Petra
authors.initials: P
authors.lastname: Dvorakova
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic;
authors.forename: Dominika
authors.initials: D
authors.lastname: Coufalova
authors.affiliation: ¶Institute of Microbiology, The Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic; ‖Department of Biochemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Prague, Czech Republic;
authors.forename: Daniel
authors.initials: D
authors.lastname: Kavan
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic; vojtesek@mou.cz muller@mou.cz.
authors.forename: Borivoj
authors.initials: B
authors.lastname: Vojtesek
authors.affiliation: From the ‡Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Zluty Kopec 7, 656 53 Brno, Czech Republic; vojtesek@mou.cz muller@mou.cz.
authors.forename: Petr
authors.initials: P
authors.lastname: Muller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D018840:HSP70 Heat-Shock Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C108485:TOMM34 protein, human; D000255:Adenosine Triphosphate