Plasticity of the protein folding landscape: switching between on- and off-pathway intermediates

Proteins may fold via parallel routes partitioned by the relative effect of solvent conditions on the relevant transition states. Thus, intermediates may or may not necessarily be obligatory species accumulated during the folding process, but rather kinetic traps due to the ruggedness of the folding landscape. Implicit in this view is the notion of plasticity of the folding pathway: proteins can be rerouted through the energy landscape by mutational, topological or solvent perturbations. Our work was specifically aimed to the experimental identification of a switch in the folding mechanism of a c-type cytochrome from the thermophilic bacterium Hydrogenobacter thermophilus (HT cyt c(552)) induced by acidic conditions. We present evidence that, by destabilizing the relevant transition state, the native state of HT cyt c(552) can be reached along alternative folding routes, which may involve an off-pathway intermediate.