An unusual protein-protein interaction through coupled unfolding and binding

Aptides, a novel class of high-affinity peptides, recognize diverse molecular targets with high affinity and specificity. The solution structure of the aptide APT specifically bound to fibronectin extradomain B (EDB), which represents an unusual protein-protein interaction that involves coupled unfolding and binding, is reported. APT binding is accompanied by unfolding of the C-terminal β strand of EDB, thereby permitting APT to interact with the freshly exposed hydrophobic interior surfaces of EDB. The β-hairpin scaffold of APT drives the interaction by a β-strand displacement mechanism, such that an intramolecular β sheet is replaced by an intermolecular β sheet. The unfolding of EDB perturbs the tight domain association between EDB and FN8 of fibronectin, thus highlighting its potential use as a scaffold that switches between stretched and bent conformations.