Abstract
The Hsp90 Chaperone Machinery
Highlights
The slow hydrolysis suggests that complex conformational rearrangements of Hsp90 are coupled to the ATPase reaction and that these represent the rate-limiting step of the enzyme
This releases a short N-terminal segment from its original position [16]. This segment binds to the respective N-domain of the other subunit in the dimer, producing a strand-swapped, transiently dimerized N-terminal conformation [5, 15]. These N-terminal rearrangements result in further conformational changes throughout the entire Hsp90 dimer leading to a twisted and compacted dimer, in which N- and M-domains associate and the distance between M-domains is shortened by 40 Å [5]
As several Hsp90 substrate proteins are kinases, which can be deregulated in the development of cancer, derivatives of Hsp90 inhibitors are currently being investigated as anticancer therapeutics at the stage of clinical trials [22]
Summary
The first steps of these conformational changes were elucidated recently in detail [15]: upon ATP binding, a short segment of the N-domain called the “ATP lid” changes its position and flaps over the binding pocket (Fig. 1, steps 2 and 3) This releases a short N-terminal segment from its original position [16]. The unusual way in which ATP is bound by Hsp is perfectly mimicked by some natural compounds, such as geldanamycin and radicicol These are highly specific and potent inhibitors of the Hsp ATPase [20], blocking the maturation of substrate proteins and eventually resulting in their degradation [21]. Both chaperones become physically linked by an adaptor protein called Hop/Sti (Table 1) This co-chaperone binds via small helical TPR domains to the C-terminal ends of Hsp and Hsp90 [26]. KD values were obtained using different techniques. n.d., not determined
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