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Review
. 2008 Aug 22;283(34):22885-9.
doi: 10.1074/jbc.R800023200. Epub 2008 May 30.

The Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts

William B Pratt  1 , Yoshihiro Morishima, Yoichi Osawa
Affiliations
Review

The Hsp90 chaperone machinery regulates signaling by modulating ligand binding clefts

William B Pratt et al. J Biol Chem. .
No abstract available

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Figures

FIGURE 1.
FIGURE 1.
Mechanism of cleft opening and GR·Hsp90·immunophilin heterocomplex assembly. The ATP-dependent conformation of Hsp70 binds initially to the GR, and in an ATP-, K+-, and Hsp40-dependent step, a GR·Hsp70 complex is formed that is primed to interact with Hsp90. After Hsp90 binding, there is a second ATP- and K+-dependent step that is rate-limiting and leads to opening of the steroid binding cleft, enabling access of the steroid (indicated by the steroid structure). During GR·Hsp90 heterocomplex assembly in cells and cell lysates, Hop and some of Hsp70 dissociate during or at the end of the cleft opening step. The GR-bound Hsp90 is now in its ATP-dependent conformation and can be bound by p23, which stabilizes the chaperone in that conformation, preventing disassembly of the GR·Hsp90 heterocomplex. When Hop dissociates, TPR domain proteins, such as immunophilins (IMM), can bind reversibly to the TPR acceptor site on GR-bound Hsp90. TPR domains are indicated by black crescents.
FIGURE 2.
FIGURE 2.
Dexamethasone-dependent transactivation under conditions of stable and dynamic GR·Hsp90 heterocomplex cycling. A, the seven-amino acid segment (dark blue band) in the LBD of the GR (numbers for rat). AD, activation domain; DBD, DNA binding domain. B, dexamethasone stimulation of transcription from a luciferase reporter in cells with wild-type (wt) and P458A/T549A/V551A (Mutant) GRs (23). C, dexamethasone stimulation of transcription from a chloramphenicol acetyltransferase (CAT) reporter in wild-type (non-acetylated Hsp90) and HDAC6 knockdown (KD; acetylated Hsp90) cells (27).
FIGURE 3.
FIGURE 3.
States of the steroid binding cleft and Hsp90 cycling. The open versus closed states of the cleft are shown in the absence of Hsp90 (A) or when there is stable complex assembly with Hsp90 (B). Steroid binding promotes closing of the cleft, converting the receptor from stable to dynamic cycling with Hsp90 (C).
FIGURE 4.
FIGURE 4.
Segment of the ErbB kinase domains determining geldanamycin sensitivity.
FIGURE 5.
FIGURE 5.
Mechanism-based inactivators trigger nNOS degradation via Hsp70-dependent ubiquitination. Mechanism-based inactivation of nNOS by certain substrates leads to unfolding of the heme/substrate binding cleft to a degree that Hsp90 cannot cycle with the enzyme to inhibit ubiquitination by Hsp70-dependent E3 ligases, such as CHIP. The solid crescent represents the CHIP TPR domain.
See this image and copyright information in PMC

References

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