Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA
* Author for correspondence (e-mail: r-morimoto{at}northwestern.edu )
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Summary |
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Key words: Signal transduction, Hsp70, Hsp90, Bag1, Nuclear hormone receptors, Kinases, Molecular chaperones, Protein folding, Protein aggregation
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Too much or too little is not good |
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Interestingly, cells that have lost their ability to regulate cell growth,
such as tumor cells, often express high levels of multiple HSPs compared with
their normal parental cells (Jaattela,
1999). Depletion of Hsp90 by geldanamycin or of Hsp70 by
anti-sense methodology in transformed cells, but not in their non-transformed
counterparts, causes either arrest of cell growth or cell death
(Nylandsted et al., 2000
;
Whitesell et al., 1994
). Tumor
cells appear to be dependent on increased levels of HSPs, although why this is
beneficial has yet to be clearly established. One possibility is the ability
of chaperones to suppress and buffer mutations that accumulate during the
transformation process, which could promote cell viability and even enhanced
cell growth of otherwise mutant cells. This is exemplified by the relationship
between p53, Hsp70 and Hsp90, where mutant forms of p53, but not wild-type
p53, depend on Hsp70 and Hsp90 for normal level and function
(Blagosklonny et al., 1996
;
Pinhasi-Kimhi et al.,
1986
).
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Hsp70 and Hsp90 are heat shock proteins |
---|
In addition to their roles in protecting cells from stress, nearly all HSPs
are constitutively expressed under normal growth conditions, where they
function to maintain protein homeostasis by regulating protein folding quality
control. The chaperone activities of heat shock proteins enable folding of
newly synthesized proteins and assist protein translocation across
intracellular membranes (Hartl and
Hayer-Hartl, 2002; Neupert,
1997
).
Here, we focus on the activities of two abundantly expressed and highly
conserved heat shock proteins: Hsp70 and Hsp90. The levels of human Hsp70 and
Hsp90 vary among primary and transformed cell lines and range from 10
µM-100 µM for Hsp70 and 10 µM to 150 µM for Hsp90 (C. Schmidt and
R.I.M., unpublished). Hsp70 and Hsp90 represent two different classes of
molecular chaperone. Whereas Hsp70 holds unfolded substrates in an
intermediately folded state to prevent irreversible aggregation and catalyzes
the refolding of unfolded substrates in an energy- and co-chaperone-dependent
reaction, Hsp90 appears to interact with intermediately folded proteins and to
prevent their aggregation but lacks the ability of Hsp70 to refold denatured
proteins. In vitro chaperone assays using chemically denatured proteins have
shown that Hsp90 is highly efficient in preventing protein misfolding and that
the Hsp70 chaperone machinery is required to fold the Hsp90-released
intermediates to the native state (Freeman
and Morimoto, 1996; Jakob et
al., 1995
; Wiech et al.,
1992
).
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Biochemical activities of Hsp70 |
---|
|
Co-chaperone interactions can influence the Hsp70-substrate
binding-and-release cycle by stimulating, inhibiting or altering the
trafficking of Hsp70-interacting substrates. Hip binds to the ATPase domain
and increases the chaperone activity of Hsp70 by stabilizing the ADP state,
which is the substrate-bound state of Hsp70
(Fig. 1a) (Hohfeld et al., 1995). Bag1,
by contrast, inhibits the chaperone activity of Hsp70 in part by accelerating
nucleotide exchange, which affects the premature release of the unfolded
substrate (Bimston et al.,
1998
; Hohfeld and Jentsch,
1997
; Takayama et al.,
1997
; Zeiner et al.,
1997
). Hip and Bag1 bind to Hsp70 at the same site on the ATPase
domain and directly compete to influence Hsp70 chaperone activity
(Fig. 1a)
(Hohfeld and Jentsch, 1997
;
Nollen et al., 2001
). The
biological role of these co-chaperones in the regulation of Hsp70, however, is
not well understood. In part, this is because the levels of Hip and Bag1 are
approximately 1% of Hsp70, and biochemical studies have shown that Bag1, for
example, affects the Hsp70 chaperone activity in a 1:1 molar ratio
(Nollen et al., 2000
;
Takayama et al., 1997
). This
would indicate that Bag1 influences only a fraction of the Hsp70 molecules in
the cell and therefore is unlikely to be an essential co-chaperone of Hsp70.
Bag-1 and Hip also interact with other proteins in the cell. Bag1, for
example, interacts with and influences the function of many key components of
cell death and signal transduction pathways, including the anti-apoptotic
protein Bcl-2 and the growth regulator Raf-1
(Takayama and Reed, 2001
;
Wang et al., 1996
). We propose
that the regulation of Bag1 function by Hsp70 serves as a checkpoint to
regulate growth and death when the levels of Hsp70 in the cell rise in
response to stress (Song et al.,
2001
).
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Biochemical activities of Hsp90 |
---|
The biochemical mechanism of Hsp90-substrate interactions is currently a
topic of active investigation, and, to date, has only partially been
characterized. Although Hsp90-substrate binding is ATP independent, substrate
release requires ATP hydrolysis (Panaretou
et al., 1998; Prodromou et
al., 1997
). The Hsp90-substrate binding-and-release cycle is
regulated by sequential interactions of Hsp90 with the co-chaperones Hop and
p23. Hop is a tetratricopeptide repeat (TPR)-domain-containing protein that
binds to the C-terminal domain of Hsp90. Binding of Hop induces a
conformational change in the ATPase domain of Hsp90 that inhibits the ATPase
activity (Prodromou et al.,
1999
). Dissociation of the Hop and Hsp70 from Hsp90, by an as yet
unknown mechanism, results in a conformational change in the ATPase domain
that enables binding of ATP and a transient dimerization of the N-termini of
Hsp90 molecules, whereas their C-terminal domains remain dimerized. In turn,
this allows for association with p23 and members of the immunophilin family,
followed by ATP hydrolysis and opening of the molecular clamp formed by the
N-terminal ends of the Hsp90 dimer to release the substrate. The
Hsp90-specific inhibitor geldanamycin competes with ATP at the ATP-binding
site and thus prevents completion of the interaction cycle by interfering with
the association of p23 and ATP hydrolysis
(Prodromou et al., 2000
;
Prodromou et al., 1999
;
Young and Hartl, 2000
). Hsp90
also associates with other co-chaperones besides Hop and p23, including other
TPR-domain-containing proteins and Cdc37
(Table 1). Many of these
co-chaperones compete for binding to the C-terminal domain of Hsp90
(Fig. 1b), which suggests that
co-chaperones might play a role in targeting Hsp90 to specific substrates.
|
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Interaction between chaperones and signaling molecules |
---|
Below we describe two examples of signaling routes in which chaperones of the Hsp90 and Hsp70 families play a role: the Ras/Raf-1 signal transduction pathway and the nuclear hormone aporeceptor complex assembly. Along with these examples we describe what is known about the role of chaperones and co-chaperones in these processes.
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Chaperones and the Ras/Raf-1 signal transduction pathway |
---|
Hsp90 has been found in association with many components and regulators of
the Ras/Raf-1 pathway, including Raf-1, Ksr-1, Akt and Src
(Kolch, 2000;
Sato et al., 2000
;
Stewart et al., 1999
;
Whitesell et al., 1994
).
Genetic studies in Drosophila and biochemical studies in mammalian
cells have demonstrated that interactions between Hsp90 and Raf-1 are
essential for Raf-1 activation. Mutations in Drosophila Hsp90 that
decrease the interaction between Raf-1 and Hsp90 suppress Raf-1
gain-of-function mutants, which affect eye development. The same mutations in
Hsp90 that suppress activated Raf-1 also reduce the biochemical activity of
activated Raf-1 (Cutforth and Rubin,
1994
; van der Straten et al.,
1997
).
Similarly, prolonged exposure of mammalian cells to the Hsp90 inhibitor
geldanamycin dissociates Raf-1-Hsp90 complexes, resulting in decreased Raf-1
activity owing to enhanced degradation of the Raf-1 protein
(Schneider et al., 1996;
Stancato et al., 1997
). By
contrast, short exposures to geldanamycin leads to Raf-1 activation,
suggesting that the transient release of Hsp90 is essential for activation.
One way to interpret the duration-dependent effects of exposure to
geldanamycin is that Hsp90 is required for maturation and maintenance of the
stability of Raf-1 but is released for activation of Raf-1 by other
regulators. Hsp90 release may even be essential for kinase activation; this
has been suggested by analogous studies on PKR, an interferon-induced
serine/threonine kinase. Hsp90 binding, although required for adoption of a
conformation primed for activation, inhibits PKR activity by binding to the
kinase domain and regulatory domain simultaneously
(Donze et al., 2001
). Deletion
of the N-terminal domain of Raf-1 results in constitutive activation,
suggesting that a conformational change of Raf-1 is required. Altogether,
these studies suggest that binding of Hsp90 is essential for maturation of
Raf-1 but that it needs to be released for activation
(Fig. 2).
|
Hsp90 binding to Raf-1 also requires the interaction with the Hsp90
co-chaperone Cdc37. Genetic studies in Drosophila and
gene-transfer-mediated overexpression studies in mammalian cells have shown
that Cdc37 is essential for Raf-1 activation. Mutations in Cdc37 have effects
on Drosophila eye development owing to impaired signaling through the
MAPK signaling pathway, whereas overexpression of Cdc37 leads to
dose-dependent activation of the wild-type but not a constitutively active
form (Y340D) of Raf-1 (Cutforth and Rubin,
1994; Grammatikakis et al.,
1999
). Expression of a C-terminal deletion mutant of Cdc37 that
can no longer bind to Hsp90 inhibits activation of Raf-1 by Src and Ras,
indicating that an interaction between Cdc37 and Hsp90 is essential
(Grammatikakis et al., 1999
).
On the basis of these studies, Cdc37-Hsp90 complexes have been suggested to
potentiate Raf-1 activation by making Raf-1 accessible to activation by
tyrosine kinases and other regulatory molecules that promote
phophorylation.
Additionally, the Hsp70 co-chaperone Bag1 has been shown to activate Raf-1
through interaction with its kinase domain
(Wang et al., 1996). Binding
and activation by Bag1 requires the C-terminal domain of Bag1, which is also
necessary for binding to Hsp70, but does not require the N-terminal
ubiquitin-like domain (Wang et al.,
1996
). Activation by Bag1 can bypass the effects of overexpression
of a dominant-negative form of Ras1, indicating that Bag1 acts independently
of Ras (Song et al., 2001
). In
contrast to Cdc37 and Hsp90, it is not known whether Bag1 is essential for
Raf-1 activation and through what mechanism Bag1 activates Raf-1. On the basis
of mutational studies and the proposed mechanisms of activation by other
interaction partners, Bag1 could activate Raf-1 in various ways: (1)
recruitment of Raf-1 to the membrane, similar to Ras activation of Raf-1; (2)
changing the conformation of the regulatory loop, as proposed for
phosphorylation mutants of Raf-1 that are independent of Ras for their
activation; or (3) stabilization of the active conformation
(Chong et al., 2001
).
Alternatively, activation of Raf-1 may require release of Hsp90. Therefore,
it is possible that Bag1 binding could either displace or replace Hsp90 to
stabilize the active conformation of Raf-1
(Fig. 3). Consistent with this
suggestion, naturally occurring variations in the expression levels of Hsp70
may serve to inactivate Raf-1 when Hsp70 forms complexes with Bag1, thus
preventing its interaction with Raf-1
(Song et al., 2001).
Altogether, chaperones and co-chaperones are essential for the maturation,
stabilization and activation of the Raf-1 kinase. Although their biochemical
roles in these processes remain to be further characterized, these may be
similar to their well established roles in steroid aporeceptor complex
formation as described below.
|
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Chaperones and nuclear hormone aporeceptor complex assembly |
---|
Most of our knowledge of interactions between chaperones and nuclear
receptors comes from biochemical studies on the glucocorticoid and
progesterone receptors. In an inactive conformation, these receptors are in a
heteromeric complex with Hsp90 and Hsp90-associating proteins. Before
receptors are bound to Hsp90, they go through several steps of chaperone and
co-chaperone interactions, which have also been shown to be essential by
genetic studies in yeast (Chang and
Lindquist, 1994; Chang et al.,
1997
; Dittmar et al.,
1998
; Duina et al.,
1996
). Initially the steroid aporeceptor interacts with Hsp70 and
Hsp40. From this Hsp70-bound state, the aporeceptor is transferred to Hsp90 by
the Hsp70- and Hsp90-binding co-chaperone Hop
(Chen and Smith, 1998
).
Release of Hop, ATP binding and binding of the Hsp90 co-chaperone p23 then
leads to the formation of the final aporeceptor complex that contains an Hsp90
dimer, p23 and immunophilins (Fig.
3) (Pratt and Toft,
1997
).
Interaction with chaperones has been suggested to be required for
stabilization of the aporeceptor conformation. Inactivation of Hsp90 by
geldanamycin, for example, leads to an increase in protease sensitivity and
degradation of glucocorticoid and progesterone receptors. Upon association of
hormone with the aporeceptor complex, the chaperone complex is dissociated,
and the receptor conformation transitions from a labile, open structure to the
stable compact DNA-binding state that can exist independently of chaperone
complexes (Pratt and Toft,
1997).
In addition to Hsp70 and Hsp90 complexes, other proteins, including the
Hsp70-co-chaperones Hip and Bag1, have been found associated with hormone
receptors (Prapapanich et al.,
1996; Zeiner and Gehring,
1995
). The role of Hip in receptor function, apart from its
interaction with the aporeceptor complex, has not been well characterized.
More is known about the role of Bag1 with respect to its interaction with
hormone receptors. Bag1, also identified as RAP46 (for receptor
associated protein 46), interacts with many nuclear
hormone receptors, including the glucocorticoid receptor, the estrogen
receptor and retinoic acid receptor (Liu
et al., 1998
; Zeiner and
Gehring, 1995
). Unlike Hsp70 and Hsp90 complexes, which bind to
the inactive receptor and are released after activation, Bag1 appears to bind
only to the activated receptors and after release of HSP complexes
(Zeiner and Gehring, 1995
).
Overexpression studies in mammalian cells indicate that Bag1 co-migrates with
the bound receptor to the nucleus and negatively regulates DNA binding and
transactivation by the glucocorticoid receptor and prevents
glucocorticoid-induced apoptosis (Kullmann
et al., 1998
; Schneikert et
al., 1999
). This activity is specific for two of the four isoforms
of Bag1, the 46 kDa and the 50 kDa isoforms, which contain an N-terminal
domain with a repeated [EEX4] motif and are expressed in the nucleus of
mammalian cells. In addition, it requires the C-terminal Bag1 domain that is
involved in binding to Hsp70, which suggests a role for Hsp70 in at least two
steps of hormone receptor function
(Schneikert et al., 2000
). In
complex with Hsp40 and Hop, Hsp70 functions in the cytosol to regulate
aporeceptor complex formation, and together with Bag1 in the nucleus, it has a
role in downregulation of the activated receptor
(Schneikert et al., 2000
).
Taken together, these observations indicate that chaperone and co-chaperone
interactions with hormone receptor are involved in both positive and negative
regulation of hormone receptor activities in a temporally and spatially
restricted manner.
In addition to components of the Ras/Raf-1 signaling pathway and hormone
receptors, a wide variety of other molecules interact with Hsp70 and Hsp90
chaperone complexes, including the heat shock transcription factor, Apaf1,
CFTR and Hepatitis B viral reverse transcriptase
(Abravaya et al., 1992;
Beere et al., 2000
;
Hu and Seeger, 1996
;
Loo et al., 1998
;
Pandey et al., 2000
;
Zou et al., 1998
). Although
little is known about the molecular regulation and role of chaperones in these
processes, mechanisms similar to the ones used for Raf-1 and hormone receptor
regulation may be used, perhaps in collaboration with additional, yet to be
identified co-chaperones.
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Perspectives: consequences of variations in levels of chaperones and co-chaperones |
---|
Several physiological, pathophysiological and environmental conditions,
including development, aging, fever and several neurodegenerative diseases
often associated with the accumulation of unfolded or misfolded proteins
result in elevated expression of all HSPs and many but not all co-chaperones
(Morimoto, 1998). Under such
conditions, it may be less important that a particular unfolded polypeptide is
associated with a specific chaperone; rather it is the conserved `holding'
function of chaperones that is essential, with triage decisions on the fate of
these substrates being determined later during recovery.
As a consequence of these changes, however, the equilibrium between
substrates, HSPs and co-chaperones is likely to be disturbed, which has
potentially profound consequences for the phenotype of the cell. Changes in
the abundance and relative levels of chaperones and co-chaperones could result
in novel combinations of HSPs, which, in turn, could redirect information flow
through the intracellular pathways and change the overall response to signals.
Whereas some pathways may become favored because of an increase in the level
of a particular co-chaperone that is specifically required for its regulation,
other pathways might be suppressed or acquire constitutive activation by the
lack of critical chaperone components. The overall effect of changes in
chaperone or co-chaperone levels on cellular and organismal phenotypes
probably depends on which chaperone or co-chaperone is affected. For example,
changes in the levels of Hsp90 by exposure of cells or organisms to
geldanamycin on in Drosophila by altering gene dosage, and Hsp70 by
mutation or overexpression, have pleiotropic and often more severe
consequences than do changes in the leels of a co-chaperone that is specific
for a subset of substrates, such as Cdc37, which preferentially interacts with
kinases. One example of a change in signaling as a consquence of altered
levels of HSPs is the inhibition of the Ras/Raf-1 signaling pathway in tissue
culture cells when the levels of Hsp70 increase in response to stress. The
increased levels of Hsp70 sequester Bag1, which disrupts the stimulatory
properties of Bag1 on Raf-1, which then results in cell growth arrest
(Song et al., 2001).
HSPs have co-evolved as integral components of signal transduction networks, in which they can function in the maturation, activation and inactivation of signaling molecules. Their involvement in a particular pathway within the network is determined by the availability and relative abundance of partner-specific co-chaperones, which will influence, in a cell-type-specific manner the natural response to physiological intracellular and extracellular signals. Consequently, we suggest that altered levels of HSPs and co-chaperones in response to stress or disease states alters how organisms integrate and respond to the flow of their normal physiological signals. Future studies in multicellular model systems will help to elucidate with greater detail the molecular basis for the pervasive role of molecular chaperones in organismal development and disease and how they respond to altered chaperone and co-chaperone levels associated with fluctuating environmental conditions and disease.
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Acknowledgments |
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