Molecular mechanism of the interaction of Hsp90 with cochaperones and clients

• Applicant: Professor Dr. Matthias Peter Mayer
• Subject Area: Biochemistry
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 422001793

The ATP dependent 90 kDa heat shock proteins (Hsp90s) are evolutionarily highly conserved and very abundant molecular chaperone that are essential in all eukaryotic cells. In cooperation with Hsp70 chaperones and, depending on the organism, more than 30 cochaperones, Hsp90s control stability and activity of many folded protein, called clients, including protein kinases, receptors, transcription factors, and a diverse set of other proteins. Many Hsp90 clients are components of essential signal transduction pathways and regulatory networks, and become only responsive to upstream signals when in complex with Hsp90 or properly folded by Hsp90. Not surprisingly, Hsp90 is involved in many human pathologies, including cancer, neurodegeneration, autoimmune diseases and infections with a wide range of pathogens, and is considered a prime drug target.The aim of this project is to further our understanding of the intricate Hsp90 machinery by (1) performing structure-function analysis of Hsp90-cochaperone complexes and Hsp90-cochaperone-client complexes, (2) screening for novel cochaperones and modifiers of the Hsp90 system necessary for the maturation of kinases in yeast, (3) analyzing the influence of posttranslational modification on conformational dynamics and function of human Hsp90. For our investigations we will use a wide range of biochemical and biophysical methods, including fluorescence techniques, hydrogen exchange mass spectrometry (HX-MS), and protein-protein interaction techniques, and genetics and molecular biology methods in baker’s yeast and mammalian cell culture.

• DFG Programme: Research Grants