Chaperones, Molecular
the ER until the sites that BiP recognizes
are buried in the folded protein (or until
the protein is retrotranslocated back to the
cytosol for degradation, a process in which
BiP also has a major role). Coimmunopre-
cipitation and cross-linking experiments
have shown that BiP may bind early in
the folding pathway, as do other Hsp70
homologs such as DnaK, but other stud-
ies support a role later during folding.
Complexes recovered by such experiments
often include other ER resident chaper-
ones as well as BiP, supporting the model
of a network of chaperone proteins act-
ing in concert to promote correct folding.
BiP can be acted upon by several different
membrane proteins with DnaJ domains
(all of which face the lumenal side of the
membrane) and these may all be involved
in BiP’s various functions. As with classic
Hsp40 proteins, they can act to stimulate
the ATPase activity of their Hsp70 part-
ner (BiP) and thus improve the efFciency
of the cycling on and off the complex of
partially folded protein. BiP is not the only
chaperone in the ER that can interact with
partially folded proteins: the PDI shares
this property, and thus may be involved in
retention of incorrectly folded proteins as
well as in the formation and isomerization
of disulFde bonds.
A more complex system exists to en-
sure that glycosylated proteins are in their
correct conformation before further trans-
port through the secretory pathway. Glycan
chains are added at selected asparagine
residues to proteins as they pass into the
ER through the membrane. These chains
have the formula Glc
where Glc is glucose, Man is mannose, and
GlcNAc is
-acetyl-glucosamine. Shortly
after these chains have been added, two
of the terminal glucoses are clipped off by
the enzymes glucosidase I and II, leav-
ing a single glucose. The presence of
this glucose makes the protein bind to
one of the two chaperones calnexin and
calreticulin, which are respectively trans-
membrane and lumenal proteins, thus
preventing their further transport from
the ER. In this state, they can also be
acted upon by another PDI called ERp57,
which itself binds to both calnexin and
calreticulin. The Fnal glucose residue on
the bound substrate is removed by glucosi-
dase II, which enables the protein’s release
from calnexin or calreticulin. If it is cor-
rectly folded, it will now exit the ER, but if
it is incorrectly folded, a terminal glucose
is added back to the protein by another en-
zyme (UDP-glucose:glycoprotein glucosyl
transferase), which only acts on proteins
that contain areas that are not folded, and
the protein will be rebound by calnexin
and calreticulin, thus reinitiating the cy-
cle of protein folding on these chaperones.
If after several cycles of this reaction the
protein has still failed to fold correctly, it
can be targeted for retrotranslocation and
degradation in the cytosol.
Examples of Substrate-speciFc Chaperones
The chaperones that have been considered
often referred to as ‘‘broad-spectrum’’
chaperones: that is, they have a range
of different substrate proteins with which
they interact. Not all chaperones are broad
range, however; some interact with only
one or a few substrates. There are many
examples of these in the literature, two of
which are considered here.
Hsp47 and Collagen Assembly
In addition to the various chaperones
present in the ER and described in the
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