Chaperones, Molecular
been shown to be capable of protecting a
number of substrates from aggregation,
whether induced by heat shock or by
chemical denaturation. However, it has not
yet been possible to demonstrate refolding
of the bound protein substrates
in vitro
implying that
in vivo
Hsp33 may interact
either with one of the known chaperone
proteins, or with a cofactor which is yet
to be identiFed. The likely function of
Hsp33 is protection of proteins, which
may be particularly susceptible to oxidative
in vivo
, and the rapid activation of
the chaperone activity of Hsp33 that takes
place when the protein is oxidized, makes
it an excellent Frst line of defense against
oxidative stress, which can act until the cell
has had time to induce a range of other
defenses that will tend to act by restoring
the normal redox potential of the cytosol.
Chaperone Networks and Protein Quality
Control in the Cell
As research into molecular chaperones has
progressed, it has moved to embrace con-
siderations not only of how the members
of individual chaperone families function,
but also how they interact with other
chaperone families within the cell. Much
emphasis is now placed on understanding
these interactions or networks. One such
network has already been discussed briefly
above: the interaction of Hsp70 and Hsp90
proteins in the activation of steroid hor-
mone receptors. Chaperone networks have
evolved to enable cells to maximize the ef-
Fciency with which they produce folded
and active proteins, a process that faces
two particular hurdles: the inefFciency im-
plicit in the folding process itself (i.e. the
extent to which proteins may Fnish up be-
coming misfolded or aggregated), and the
fact that folding can be reversed by stresses
such as heat shock. These networks also
have to be integrated with the cell’s mech-
anisms for disposing of proteins that are
not functional. In the next two sections, we
will look at two of the best understood of
these: the system of protein quality control
in the
E. coli
cytosol, and the system in the
ER of eukaryotic cells. Neither of these,
it must be emphasized, is yet completely
Chaperone Networks and Protein
Quality Control in the
E. coli
It has already been pointed out in the
text above that DnaK (one of the Hsp70
protein homologs in
E. coli
unrelated protein trigger factor cooperate
in chaperoning proteins that are still in
the process of being synthesized on the
ribosome. This is an essential process,
and the trigger factor and DnaK must
signiFcantly overlap in the roles that they
play in it, as demonstrated by the fact
that loss of both genes together is lethal
to the cell, whereas loss of either gene
individually is not. It is likely that in
normal cells, they act sequentially, with
the trigger factor binding to proteins as
they Frst emerge from the ribosome, and
DnaK interacting with a subset of these
later during synthesis.
Other interactions may exist between the
DnaK and the GroEL chaperone systems.
In vitro
studies using puriFed substrate
proteins have demonstrated that proteins
can be transferred between these two
systems effectively in either direction.
in vivo
evidence for a network
between these two proteins is lacking, how-
ever, except inasmuch as a few proteins
have been identiFed by coimmunoprecip-
itation experiments as being substrates of
both systems.
More direct evidence exists to link the
sHSPs of
E. coli
with the Hsp70 and Hsp60
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