Chaperones, Molecular
501
4.2
The Hsp70 Family
4.2.1
Introduction to the Hsp70 Family
The Hsp70 proteins comprise a large fam-
ily, often with many representatives in a
given organism (the yeast
Saccharomyces
cerevisiae
has 14 Hsp70 homologs). They
are found in all eubacteria, all eukaryotes,
and most archaea. The Hsp70 proteins
are all approximately 70 kDa in size, and
show a high degree of sequence similarity.
They act in concert with another family of
chaperones, the Hsp40 proteins. These are
more heterogeneous in size, and include
both soluble and integral membrane pro-
teins. All of the Hsp40 family members
possess a particular domain (referred to as
a J domain, named after DnaJ which is
one of the
E. coli
homologs of this pro-
tein), which is key to their activity. In
eukaryotic cells, both proteins are found
in many different cellular environments,
including the cytosol, nucleus, mitochon-
dria, chloroplasts, and the lumen of the
endoplasmic reticulum. They have a mul-
tiplicity of roles, all of which are related
to their ability to bind to short stretches
of hydrophobic residues in unfolded pro-
teins. As with the Hsp60 proteins, their
reaction cycle is driven by the binding and
hydrolysis of ATP, but their mode of action
appearstobeverydifferent
.Theyutilizea
wide variety of cochaperones and other fac-
tors, and are integrated into a network of
interactions with other chaperones in the
cell, as described below. Although orig-
inally described as heat shock proteins,
some members of the family are syn-
thesized constitutively and show no heat
shock induction.
4.2.2
Cellular Roles of the Hsp70 Family
The Hsp70 proteins, together with the
Hsp40 proteins, fulFll many functions
inside the cell, as expected from the
large
number
of
homologs
that
can
exist for these proteins in even a single
organism. It is clear that not all of
these functions have yet been deFned.
Some of the cytosolic members of the
family are involved in binding nascent
polypeptides as they emerge from the
ribosome, probably thereby preventing
them from folding prematurely before
the whole chain has been synthesized.
Other roles in the cytosol include the
uncoating of clathrin from clathrin-coated
vesicles, and the delivery of proteins to
the mitochondrial and chloroplast import
complexes. In the endoplasmic reticulum,
the Hsp70 homolog Bip has a key role in
ensuring that only correctly folded proteins
are delivered to the secretory pathway,
and that incorrectly folded proteins are
returned to the cytosol for destruction by
the proteasome. In the mitochondria and
chloroplasts, the organellar homologs of
the Hsp70 and Hsp40 proteins have a key
role in the uptake of proteins that are
synthesized in the cytosol and targeted
to organelles, as well as in assisting
the folding of proteins encoded by the
organellar genomes.
That these roles vary in their importance
can be seen from genetic studies. The
main Hsp70 homolog in
E. coli
,Dn
aK
,
can be deleted, and although the resultant
cells show reduced viability and no ability
to grow at high or low temperatures,
they are capable of growth at normal
temperatures. The loss of viability is in
part due to the fact that DnaK has a role in
regulation of the heat shock response, and
if the same deletion is made in
Bacillus
subtilis
, an organism where DnaK does
not have this role, the effect on viability
is reduced. Two interpretations of these
data are possible: one is that DnaK fulFlls
roles of relatively minor importance; the
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