Chaperones, Molecular
507
4.4
The Small Heat Shock Proteins
4.4.1
Introduction to the Small Heat
Shock Proteins
The small heat shock proteins (sHSPs)
are a much more diverse group of chaper-
ones than those considered above, and are
correspondingly less characterized. They
range in size from 15 kDa to greater than
40 kDa, and the degree of sequence sim-
ilarity between them is lower than that
for other chaperone families. All possess
a conserved domain of approximately 90
amino-acyl residues near the C-terminal
end, and all assemble into large oligomers,
although again the sizes of these can vary
considerably, even for a single sHSP. Or-
ganisms often contain numerous genes for
sHSPs (plants are particularly abundant in
them) and in eukaryotes they have been
found in the cytosol, the ER lumen, and in
mitochondria and chloroplasts.
4.4.2
Cellular Roles of sHSPs
The precise cellular role of the sHSPs
has proven hard to pin down. Strains of
E. coli
or
S. cerevisiae
with all their sHSP
genes deleted show very little signiFcant
phenotype unless the deletions are com-
bined with other mutations, although in
some organisms there is a reduction in
thermotolerance when sHSPs are deleted.
This lack of phenotype is a surprise, given
that the sHSPs are often among the most
strongly induced genes by heat shock.
Overexpression of sHSPs has been shown
to enhance thermotolerance in some cases,
which does support the hypothesis that
sHSPs have a role to play in survival of
temperature stress. They are often found
associated with protein aggregates, which
have arisen either from the overexpression
of proteins that failed to fold correctly,
through heat stress or through disease
states. There is also evidence that they
may play a role in aspects of cytoskeletal
and intermediate Flament assembly.
A particularly interesting example of
the sHSPs is the
α
-crystallin group of
proteins, which are very abundant in
the eye lens. Given that the eye lens is
effectively a concentrated protein solution,
which has to be kept clear for the
lifetime of the organism (as cells laid
down in fetal development remain in
the center of the lens), the avoidance
of protein aggregation is of particular
importance. Loss of acuity of vision with
age, and cataract formation, in particular,
are associated with a breakdown in the
ability of the
α
-crystallins to act effectively
as chaperones. But defects in
α
-crystallin
function have other consequences as well,
showing that its importance is not limited
to the eye lens. ±or example, the inherited
disease desmin-related myopathy, which
leads to muscle weakness, has been found
in some cases to be associated with
mutations in one of the
α
-crystallins,
and probably results from defects in
intermediate Flament assembly.
4.4.3
Mechanism of Action of sHSPs
Despite the lack of a clear
in vivo
role,
sHSPs have been demonstrated to have
chaperone activity
in vitro
, in that they are
able to bind and stabilize unfolded proteins
and prevent their aggregation. The range
of proteins that sHSPs can bind is very
large, with no apparent limits on the size
of the protein. There is no clear evidence
that sHSPs are able to assist in folding
per
se
, and the current view is that they act
predominantly as reservoirs of unfolded
protein, holding it in a nonaggregated
state until conditions more favorable for
folding are restored. Refolding of the
bound proteins may occur either after the
proteins are released into free solution, or
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