Hsp90 functions as a molecular chaperone – i.e. a “folding-helper” – when cells are under stress conditions. Most of the protein kinase family that regulate, e.g., cell growth are client proteins of Hsp90, and dysfunction of Hsp90 leads to various human diseases, such as cancer, cystic fibrosis, and Alzheimer’s. Hsp90 has thus become a promising target for drug development in recent years.

To understand communication pathways in this complex protein machinery, Kaila and co-workers combined a broad range of modern biophysical and biochemical methods that allowed the scientists to understand chemical principles responsible for its biological function. The researchers discovered how the energy of splitting ATP molecules in its catalytic core is used to power large-scale conformational changes in protein structure that are necessary for the chaperone function. The researchers further engineered mutations in the protein to block such conformational changes from taking place. They also found a unique chemically modified methyl-lysine protein residue in Hsp90 that provides an important switch point in regulating the protein function.

The study provides a basic understanding of how enzymes use chemical energy to establish biological function, and new information that can be used to design drug molecules. The Kaila group has discovered similar long-range communication pathways also in other proteins, e.g., complex I responsible for cell respiration in mitochondria, the powerplants of our cells. The findings may thus reflect general chemical principles employed by proteins to establish biological function.

The studies were performed is collaboration between Ville Kaila, Professor of biochemistry at Stockholm University, and Johannes Buchner, Kathrin Lang, and Michael Sattler, Professors at Technical University of Munich. The studies were supported by the German Research Foundation (DFG) via the collaborative research center, SFB1035.

The two studies were published in Nature Communications on March 6 and March 16:

Publication on how chemical energy powers the Hsp90 machinery

Mader SL, Lopez A, Lawatscheck J, Luo Q, Rutz DA, Gamiz-Hernandez AP, Sattler M, Buchner J, Kaila VRI (2020). Conformational dynamics modulate the catalytic activity of the molecular chaperone Hsp90. Nature Communications doi: 10.1038/s41467-020-15050-0


Publication on how a methylated Lys function as switch point for regulation of Hsp90

Rehn A, Lawatscheck J, Jokisch ML, Mader SL, Luo Q, Tippel F, Blank B, Richter K, Lang K, Kaila VRI, Buchner J (2020). A methylated lysine is a switch point for conformational communication in the chaperone Hsp90. Nature Communications 11(1):1219.  doi: 10.1038/s41467-020-15048-8.


Link to the Kaila Lab


Caption: The heat shock protein-90 (Hsp90) is a molecular chaperone that helps other proteins to fold into their correct three-dimensional structure in the eukaryotic cell. The Kaila team in collaboration with researchers in Germany identified key communication pathways in Hsp90 that transmit conformational changes across large distances that is important for the chaperone function. The two studied were published in March 6 and 16 editions of Nature Communications. Picture by Sophie Mader.