A protein-folding reaction under kinetic control

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Abstract
SYNTHESIS of α-lytic protease is as a precursor containing a 166 amino-acid pro region1 transiently required for the correct folding of the protease domain2–4. By omitting the pro region in an in vitrorefolding reaction we trapped an inactive, but folding competent state (I) having an expanded radius yet native-like secondary structure. The I state is stable for weeks at physiological pH in the absence of denaturant, but rapidly folds to the active, native state on addition of the pro region as a separate polypeptide chain. The mechanism of action of the pro region is distinct from that of the chaperonins5,6: rather than reducing the rate of off-pathway reactions, the pro region accelerates the rate-limiting step on the folding pathway by more than 107. Because both the I and native states are stable under identical conditions with no detectable interconversion, the folding of α-lytic protease must be under kinetic and not thermodynamic control.