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Significance Much of our current knowledge on protein folding is based on work focused on isolated domains. In this study, using a combination of NMR and kinetic experiments, we depict the folding pathway of a multidomain construct comprising two PDZ domains in tandem, belonging to the protein Whirlin. We demonstrate the presence of a misfolded intermediate that competes with productive folding. Interestingly, we show that, unexpectedly, this misfolded state retains the native-like functional ability to bind its physiological ligand, representing a clear example of a functionally competent misfolded state. On the basis of these results and a comparative analysis of the amino acidic sequences of Whirlin from different species, we propose a possible physiological role of the misfolded intermediate.

Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate