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Cryo- EM Helps Determine Characterisation of an HSP90 co-Chaperone
Jul 04 2018 Read 528 Times
The structure of a key protein folding assistant has been solved to a resolution of 3.6 Å, using cryo-electron microscopy (cryo-EM) at the Electron Bio-Imaging Centre (eBIC) at Diamond. The structure* demonstrated that the co-chaperone possessed remarkable flexibility which allowed HSP90 to interact with a diverse range of client proteins.
Large protein complexes in cells, such as some kinases and polymerases, are often assembled with the assistance of a molecular chaperone known as HSP90. Many of the complexes assembled by HSP90 control cell growth and are implicated in cancer, so HSP90 inhibitors are currently being evaluated in clinical trials.
Surprisingly, HSP90 needs a co-chaperone called the R2TP/Prefoldin-like (R2TP/PFDL) complex in order to function properly, yet the exact way that this co-chaperone interacts with HSP90 is unclear. To fully understand its role, a collaborative effort between scientists from Spain and the UK set out to characterise the R2TP core. They conducted cryo-EM to solve the structure of the large multi-subunit protein to a resolution of 3.6 Å.
The team noted that the R2TP core differed from its yeast equivalent as it contained a domain at the C-terminus of RPAP3, the HSP90 recruiting component on R2TP, which tightly anchors RPAP3 to R2TP. This tight binding at the C-terminus frees the HSP90-binding domains in RPAP3 at the N-terminus, providing a flexible tether to HSP90, which allowed it to act on a diverse range of client proteins. Fully understanding how HSP90 and its co-chaperone supports the assembly of proteins involved in cancer might bring us a step closer to the development of a new series of anticancer agents.
*As detailed in Nature Comunications.
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