A switch point in the molecular chaperone Hsp90 responding to client interaction

• Published in: Nature communications 2018-04, Vol.9 (1), p.1472-14, Article 1472
• Main Authors: Rutz, Daniel Andreas, Luo, Qi, Freiburger, Lee, Madl, Tobias, Kaila, Ville R. I., Sattler, Michael, Buchner, Johannes
• Format: Article
• Language: English
• Subjects: 101/6; 119/118; 631/1647/2196/2197; 631/337/470/1981; 631/45/612/1981; 82/80; 82/83; 96/33; Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Amino Acid Sequence; Amino Acid Substitution; Animals; Binding Sites; Caenorhabditis elegans - chemistry; Cloning, Molecular; Crystallography, X-Ray; Escherichia coli - genetics; Escherichia coli - metabolism; Gene Expression; Genetic Vectors - chemistry; Genetic Vectors - metabolism; Heat shock proteins; HSP90 Heat-Shock Proteins - chemistry; HSP90 Heat-Shock Proteins - genetics; HSP90 Heat-Shock Proteins - metabolism; Hsp90 protein; Humanities and Social Sciences; Humans; Ligands; Lysine; Lysine - chemistry; Lysine - metabolism; Mice; Molecular Dynamics Simulation; multidisciplinary; Mutation; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Saccharomyces cerevisiae - chemistry; Science; Science (multidisciplinary); Sequence Alignment; Structural Homology, Protein; Tryptophan; Tryptophan - chemistry; Tryptophan - metabolism; Zebrafish - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03946-x

Heat shock protein 90 (Hsp90) is a dimeric molecular chaperone that undergoes large conformational changes during its functional cycle. It has been established that conformational switch points exist in the N-terminal (Hsp90-N) and C-terminal (Hsp90-C) domains of Hsp90, however information for switch points in the large middle-domain (Hsp90-M) is scarce. Here we report on a tryptophan residue in Hsp90-M as a new type of switch point. Our study shows that this conserved tryptophan senses the interaction of Hsp90 with a stringent client protein and transfers this information via a cation–π interaction with a neighboring lysine. Mutations at this position hamper the communication between domains and the ability of a client protein to affect the Hsp90 cycle. The residue thus allows Hsp90 to transmit information on the binding of a client from Hsp90-M to Hsp90-N which is important for progression of the conformational cycle and the efficient processing of client proteins. The heat shock protein 90 (Hsp90) chaperone undergoes large conformational changes during its functional cycle. Here the authors combine in vivo, biochemical, biophysical and computational approaches and provide insights into the allosteric regulation of Hsp90 by identifying and characterizing a switch point in the Hsp90 middle domain.