Cryo-EM of multiprotein complexes (360G-Wellcome-095605_Z_11_A)

The Hsp90 molecular chaperone plays an essential role in the stabilisation andactivation of a wide range of client' proteins, including some of the most important proteins required for cell maintenance and regulation in eukaryotic organisms from yeast to humans. Hsp90 itself is regulated by a plethora of co-chaperone proteins that modulate its essential ATPase coupled conformational cycle, and/or act as adaptors facilitating recruitment of specific client proteins to the Hsp90 machinery. Involvement of Hsp90-dependent clients in the development and progression of cancer, has led to enormous interest in Hsp90 as a drug target, and an emerging realisation of Hsp90 involvement in viral and and parasitic infections, suggests that Hsp90 is important in many other diseases. Although much of the biochemistry of the Hsp90 system has been unravelled in recent years, central questions of Hsp90 biology remain unanswered. To address this, we propose to define at the structural level the molecular mechanisms by which the Hsp90 molecular chaperone system contributes to the activation, stabilization and regulation of its selected client' proteins in eukaryotic cells