Chaperones, Molecular
491
it would in theory take, on an average,
billions of years of searching through
all the different conformational options
for a given protein molecule to Fnd the
most stable conformation. It is known,
however, that proteins can fold from the
denatured state over a timescale of mi-
croseconds to seconds. To resolve this
apparent paradox, Levinthal proposed that
folding pathways exist, with a limited num-
ber of possible conformations existing
along the pathways.
This view is still thought to be essentially
correct, but the view of a folding pathway
has been reFned to that of an energy
landscape. According to this view, the
folding of a protein is analogous to the
trajectory taken by a ball that is rolling
around on a rubber sheet, which has been
deformed by a heavy weight. The ball will
eventually Fnish up at the bottom of the
dip caused by the heavy weight; this is
equivalent to the protein in its lowest
energy conformation. The precise route
that the ball takes to get to the bottom of
the well depends on a number of factors,
such as its initial starting point and the
shape of the distorted sheet. Similarly,
within a given population of proteins,
some molecules may fold very rapidly and
others more slowly. The fact that they all
Fnish up in the same Fnal conformation
does not imply that they all have to follow
precisely the same pathway to get there.
This view of protein folding can be fur-
ther expanded to consider what events
might lead to some proteins failing to reach
a fully folded and active conformation. At
least two such events can be envisaged,
leading respectively to protein misfold-
ing and to protein aggregation. In the
case of protein misfolding, the polypeptide
chain may reach a metastable state where
it is indeed folded but has not reached
its correct and active conformation, and
cannot proceed to it on a biologically rel-
evant timescale. In the case of protein
aggregation, the protein may have formed
interactions with other partially folded pro-
tein chains such that all these proteins are
now held together but are inactive because
they have not reached their fully folded
states. Interestingly, aggregation appears
to be speciFc in that, when it occurs in
mixtures of proteins, similar or identical
proteins will tend to aggregate with each
other. Aggregation is particularly likely to
be a problem where protein concentrations
are high, since the likelihood of two pro-
teins interacting with each other before
they fold into the native state is greater.
Aggregation is potentially a particularly
serious problem for proteins, because the
forces that drive protein folding (hydropho-
bic forces) are the same as the forces that
lead to protein aggregation. It is also a
problem inside the cell, where protein con-
centrations may be extremely high.
Aggregation and misfolding are not
the only problems that may be faced
by proteins as they fold within the cell
(┬▒ig. 1). Another difFculty for proteins
is that many targeting events require
proteins to cross membranes into different
cellular compartments, and yet it is hard to
envisage a more effective barrier to a folded
protein than a lipid bilayer. In order to
cross membranes, proteins generally need
to be prevented from folding but protected
from other folding proteins with which
they might interact both before and after
they have crossed the membrane. Proteins
also often need to form interactions with
a large array of cofactors and effectors,
and may require the presence of these in
order to adopt their active conformations.
In this event, proteins would need to
be synthesized but kept in a receptive
state until the cofactor becomes available.
Proteins on the secretory pathway in
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