Chaperones, Molecular
515
previous section, another chaperone pro-
tein called Hsp47 is also present. This
protein is required for the chaperoning of
one class of proteins only: the collagens.
Collagens are the most abundant proteins
in mammals, and the importance of the
action of Hsp47 is shown by the fact that
mice with both copies of the
hsp47
gene
disrupted do not survive to term and show
many abnormalities in collagen process-
ing, which has numerous lethal effects on
tissue integrity. How does Hsp47 act? To
answer this question, we need to know
something about collagen assembly.
Although there are large numbers of dif-
ferent types of collagen, they share certain
common features. Collagen is synthesized
as procollagen, which contains domains
at both the N- and C-termini, which are
removed in the formation of the mature
collagen molecule. These N- and C-termini
form globular domains while the rest of the
procollagen molecule forms alpha-helices,
three of which coil around each other to
form the characteristic collagen triple he-
lix. The alpha-helices consist of repeats of
themo
t
ifG
-X
-Y
,whereYisof
tenpro
l
ine
(or hydroxyproline, formed in the ER from
proline). This molecule is then transported
to the Golgi body and ultimately to the
cell surface, where the N- and C-terminal
domains are removed and collagen triple
helices become associated via unknown
mechanisms into long Fbrils. Hsp47 has
been shown to bind to the triple-helical
procollagen molecule, and this binding re-
quires the presence of at least one arginine
residue in the triple helix. The precise
role of the Hsp47 binding is not yet clear,
but one promising hypothesis is that it
prevents the premature aggregation of pro-
collagen molecules into larger Fbrils, that
would not be exportable from the ER. In-
triguingly, Hsp47 has been shown to be
capable of forming trimers, and one specu-
lation is that it may form rings around the
triple-helical procollagen molecules that
could serve to prevent lateral aggregation
with other procollagens.
5.3.2
PapD and the Assembly of Bacterial
Pili
The interactions of chaperones and sub-
strates generally lack the degree of speci-
Fcity that is commonly associated with pro-
tein–protein interactions, and it is this lack
of speciFcity that contributes to the broad
range of substrates on which chaperones
can act. However, the substrate-speciFc
chaperones, such as Hsp47 above, must
be able to recognize and act on particular
substrates. In one group of proteins, the
so-called PapD chaperones, the molecular
basis for this recognition is understood,
and this gives us useful insights into how
such chaperones can act.
PapD chaperones are members of a
superfamily of proteins, found in the
periplasm of different bacteria, which
are involved in the assembly of pili and
other surface structures. This gives them
considerable applied interest because pili
and Fmbrae play a major role in the
attachment of bacteria to surfaces and in
many cases this makes them important
virulence factors in disease. More than 30
members of this superfamily are known.
PapD is one of the best studied of these and
was distinguished as the Frst chaperone
(albeit one whose action is highly speciFc)
for which a crystal structure was obtained.
Certain strains of
E. coli
produce so-
called P pili, which are complex structures
consisting of an adhesion protein (PapG)
at the tip of the pilus, joined via an adaptor
protein (Pap±) to a string of subunits
(of the PapE protein) in an open helical
conformation, which in turn are linked by
another adaptor protein (PapK) to another
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