• Publié par : Christian DELAMARCHE
  • Imprimer cette page

Structure/function of molecular chaperones

The 90-kDa chaperone protein (Hsp90) is highly conserved and ubiquitously expressed in most living organisms. Hsp90 is essential for cell survival in eukaryotes, as it is required for the folding and regulation of many key proteins involved in signal transduction and cell cycle control. Besides its highly flexible dimeric state, heat shock protein Hsp90 is able to self-oligomerize in the presence of divalent cations or under heat shock. In addition to dimers, oligomers exhibit a chaperone activity.
The functional and structural study of Hsp90 presents both fundamental and applied interests. In this project we will focus on the following crucial questions: What are the Hsp90 dynamics during the chaperoning cycle? What is the structure of oligomeric species, and how do they participate to the Hps90 chaperoning cycle? What are the changes in Hsp90 clients engendered by association with Hsp90? What are the effects of inhibitors on Hsp90 structure and on the stability of Hsp90 oligomers and Hsp90-co-chaperones complexes?
Unravelling the Hsp90 chaperone cycle will be achieved only when the roles of all the actors, i.e., the Hsp90 dimer and oligomers as well as co-chaperones and ligands will be taken into account.
The study will combine analytical ultracentrifugation, size exclusion chromatography coupled to multi-angle laser light-scattering, and high-mass MALDI-TOF MS to determine biochemical and biophysical characteristics of each Hsp90 oligomer. Their structures will be determined using electron microscopy. The influence of new synthesized inhibitors on Hsp90 structure and function will be studied.