Chaperones, Molecular
505
it binds to the SHR, which then dissociates
from Hsp90, dimerizes, and enters the nu-
cleus. Other proteins, such as the eIF-2
α
kinase, are bound by Hsp90 and released
to become fully folded only after phos-
phorylation. The fact that Hsp90 is also
a heat shock protein suggests that it may
also have an important role in protecting
cells, and it has been shown
in vitro
that it
can bind to and prevent the aggregation of
proteins under thermal stress.
The high levels and essential nature
of cytosolic Hsp90 point to some other
specialized function, and a clue as to
what this might be has come from recent
remarkable experiments that have shown
that Hsp90 may be able to buffer potential
phenotypic variation that is present, but
not expressed, in all cells. When levels of
Hsp90 activity are intentionally lowered,
either genetically or by various external
treatments, it is found in both plant
and animal models that the degree of
phenotypic variability seen is increased.
Different alterations in phenotype are
seen even between organisms that are
genetically identical. Thus, it appears that
Hsp90 may act to reduce ‘‘noise’’ that
is present when organisms develop due
to chance fluctuations in environmental
conditions or small genetic differences,
and this noise can be revealed when Hsp90
activity is compromised. It has even been
speculated that this noise suppression
may be a mechanism that has evolved
to increase the amount of phenotypic
variation present and expressed in a
population at times of stress, where rapid
evolution may be important for survival.
4.3.3
Mechanisms of Action of the Hsp90
Family
The way in which Hsp90 proteins bind to
their substrates, and subsequently release
them under the control of a suitable sig-
nal, is not well understood. What is clear is
that the reaction mechanism in the cell is
very distinct from those considered above,
in that many more cellular cochaperones
are involved. The folding cycle for SHRs
has been particularly closely studied, and
appears to begin with the partially folded
SHR binding to Hsp70. Hsp70 can itself
associate with a number of different cofac-
tors
in vivo
, and one of these, referred to as
Hop or Sti1 depending on the organism,
mediates the binding of Hsp70 to Hsp90.
The SHR is then transferred to Hsp90 and
the Hsp70 and Hop components leave the
complex. The SHR is at this stage still not
competent to bind steroid hormone. Be-
fore it can become so, at least two other
components associate with the Hsp90: a
protein called p23, and one of a number of
proteins that are peptidyl–prolyl cis–trans
isomerases (PPIases). Both of these pro-
teins have chaperone activities of their
own, and the combined effect of all these
proteins coming together is to alter the
conformation of the bound SHR such that
it can now bind steroid hormone. These
reactions are shown in outline in Fig. 5.
A good deal of attention has focused on
these latter stages in the binding cycle, as
th
e
r
ew
a
sf
o
rs
om
et
im
eac
on
t
r
o
v
e
r
s
y
about the role of ATP in the action
of Hsp90. Hsp90 tested
in vitro
does
not appear to require either binding or
hydrolysis of ATP in order to act as a
chaperone, but nevertheless contains an
ATP binding site, deletion of which is
lethal
in vivo
.I
tnowappearstha
tHsp90
cannot bind to the PPIases or p23 until
ATPisbound
.AsHsp90hasapo
ten
t
ia
l
role in the cell cycle, promoting the folding
of some of the kinases needed for cell
cycle control, its inhibition in rapidly
proliferating cells has been seen as a
potential anticancer strategy. Some drugs
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