498
Chaperones, Molecular
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Fig. 2
Refolding of a denatured protein
in vitro
by GroEL, GroES, and ATP. In
the example shown here, a substrate protein has been denatured in buffer using
heat, and then returned to the temperature at which it is normally active. At
suitable time points, the protein is assayed for regain of enzyme activity. The
square symbols show the effect in buffer alone, and demonstrate that this
particular substrate cannot effectively renature under the conditions shown. The
diamond symbols show the effect of having GroEL, GroES, and ATP present in
the buffer, with the GroEL and GroES at the same molar concentration as the
substrate protein. As can be seen, this addition leads to restoration of roughly
80% of the initial activity of the protein.
at least three different models to explain
how this process helps the protein to
fold, and these are not mutually exclusive.
The Frst (referred to sometimes as the
‘‘AnFnsen cage’’ model) proposes that the
enclosed cavity simply provides a passive
and protected environment where the
protein can fold without interacting with
other folding proteins with which it might
otherwise aggregate. A reFnement of
this model (the ‘‘assisted folding’’ model)
suggests that the environment of the cage
is important, as the interior surface of the
cage is rich in hydrophilic residues that
tend to favor the burial of hydrophobic
residues in the encapsulated substrate
protein, thus accelerating folding. A third
model (the ‘‘iterative annealing’’ model)
suggests a very different role for GroEL. In
this model, the principal role of GroEL
is to
unfold
proteins that have become
trapped in nonproductive misfolded states,
and to redeliver them to the start of
the protein folding pathway. It is quite
possible that elements of all three models
are correct, and that the extent to which any
one applies varies with different substrate
proteins. ±urther reFnements to these
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