Chaperones, Molecular
termed GrpE in
E. coli
, which catalyzes the
exchange reaction and allows the cycle to
be completed with the release of bound
protein and the regeneration of the Hsp70-
ATP form. GrpE homologs are found in
archaea, mitochondria, and chloroplasts,
while other proteins that catalyze the same
kind of nucleotide exchange, such as Bag-
1, are found in eukaryotes.
Structure and Function of the
Hsp70/Hsp40 Family
Hsp70 is a two-domain protein, with one
domain containing the ATP binding site
and the other domain containing the
peptide binding site. To date, no structure
for the whole protein is available, but
structures of the individual domains are
known. The peptide binding domain has
been crystallized with a bound peptide in
place, and this structure shows that the
peptide binds to a hydrophobic groove
in the chaperone. The bound peptide is
held in place by an
-helix, the position of
which is thought to change depending on
the nucleotide-binding state of the other
domain, thus explaining how Hsp70 can
change between a low-afFnity and a high-
afFnity state depending on the presence
of ATP. Hsp40 proteins can also bind
peptides with high afFnity, and structural
studies on the conserved J domain shared
by all these proteins show that again this
binding is to a hydrophobic groove. The
features that determine afFnity of peptides
for the grooves on these two proteins are
essentially the same – consistent with the
model that Hsp40 binds peptides (or, in
the cell, stretches of unfolded protein with
the appropriate amino acids present) Frst
and then transfers them to Hsp70. The
complete structural details of the complex
formed by these two proteins are not
known, however, so the Fne details of this
mechanism are not yet understood.
The Hsp90 Family
Introduction to the Hsp90 Family
The two chaperone families we have
looked at so far have beneFted from
extensive study using simple prokaryotic
systems, and many important features
of the chaperones are conserved in both
prokaryotic and eukaryotic organisms. The
situation is somewhat different with the
Hsp90 family, a family of well-conserved
proteins of approximately 90 kDa, in that
studies on prokaryotes show that loss of the
gene does not in general produce a
strong phenotype, whereas in eukaryotes
the gene is essential. In eukaryotes, there
are several genes encoding members of
this family: the minimum number in
complex organisms seems to be two very
closely related forms in the cytosol, one
in mitochondria, and one in the ER,
although in
S. cerevisiae
the ER homolog
is not present. Hsp90 proteins are very
abundant, and are further induced by heat
shock, and they have a rather broad range
of cellular functions. Many of these are
related to the ability of Hsp90 to hold
proteins in a state that is not completely
folded or active but which is competent
to become so on the reception of a
suitable signal.
Cellular Roles of the Hsp90 Family
Many substrates for eukaryotic Hsp90 pro-
teins have been identiFed, and of these
a large proportion are involved in some
form of signaling. The best character-
ized of these are the steroid hormone
receptors (SHRs), which are proteins that,
when bound to their substrate (steroid hor-
mones), enter the nucleus and stimulate
the transcription of speciFc genes. Hsp90
holds these proteins in an inactive form
until the hormone is available, whereupon
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