An Unusual Protein-Protein Interaction through Coupled Unfolding and Binding

Abstract

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 extradomainB (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 strand of EDB, thereby permitting APT to interact with the freshly exposed hydrophobic interior surfaces of EDB. The -hairpin scaffold of APT drives the interaction by a -strand displacement mechanism, such that an intramolecular sheet is replaced by an intermolecular 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.