506
Chaperones, Molecular
1
4
3
2
90
90
90
90
90
90
90
90
K
K
HOP
SHR
SHR
SHR
SHR
p23
PPIase
p23
PPIase
SHR
HOP
To
nucleus
Fig. 5
Outline of the reaction cycle for Hsp90 binding to steroid hormone receptor (SHR).
The SHR is delivered to the Hsp90 dimer by Hsp70 in a complex with Hop protein (step 1).
SHR is transferred to Hsp90 (step 2), and p23 and PPIase associate (step 3). The precise
order of reactions and the stoichiometry of the different proteins are uncertain. SHR can
now bind to steroid hormone, which causes it to dissociate from Hsp90 and enter the
nucleus to activate gene transcription (step 4).
that have been shown to inhibit Hsp90, in
particular, the compound geldanamycin,
appear to act as competitive inhibitors of
ATP-binding, blocking the access of ATP
and hence blocking the later stages in the
Hsp90 reaction cycle.
4.3.4
Structure and Function of the Hsp90
Family
The structure of the complete Hsp90
protein is not known, but the structure of
the N-terminal domain, which is the main
site for binding of ATP, has been solved.
As with other chaperones there is evidence
of large conformational changes occurring
on ATP-binding, but the structural details
of these are unknown. Hsp90 is active as
a dimer, with the dimerization domain
in the C-terminal part of the protein,
while the N-terminal regions may have
a clamp activity, perhaps with the binding
of a nucleotide causing the opening and
closing of the clamp. Remarkably, it
appears that there are likely to be peptide
binding sites and ATP binding sites in
both the N- and the C-terminal regions of
the protein, but the functional signiFcance
of this is not understood.
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