Unfolded conformations of alpha-lytic protease are more stable than its native state

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alpha-Lytic protease (alpha LP), an extracellular bacterial protease, is synthesized with a large amino-terminal pro-region that is essential for its folding in vivo and in vitro [1,2]. In the absence of the pro-region, the protease folds to an inactive, partially folded state, designated 'I'. The pro-region catalyses protease folding by directly stabilizing the folding transition state (>26 kcal mol-1) which separates the native state 'N' from I [1,3]. Although a basic tenet of protein folding is that the native state of a protein is at the minimum free energy [4], we show here that both the I and fully unfolded states of alpha LP are lower in free energy than the native state. Native alpha LP is thus metastable: its apparent stability derives from a large barrier to unfolding. Consequently, the evolution of alpha LP has been distinct from most other proteins: it has not been constrained by the free-energy difference between the native and unfolded states, but instead by the size of its unfolding barrier.

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