Protein–protein interaction through β-strand addition

Protein–protein interactions have essential roles at almost every level of organization and communication in living cells. During complex formation, proteins can interact via covalent, surface–surface or peptide–surface contacts. Many protein complexes are now known to involve the binding of linear motifs in one of the binding partners. An emerging mechanism of such non-covalent peptide–surface interaction involves the donation or addition of a β strand in the ligand to a β sheet or a β strand in the receptor. Such ‘β-strand addition’ contacts can dictate or modulate binding specificity and affinity, or can be used in more promiscuous protein–protein contacts. Three main classes of β-strand addition can be distinguished: β-sheet augmentation; β-strand insertion and fold complementation; and β-strand zippering. A survey of protein–protein complexes in the protein data bank identifies β-strand additions in many important metabolic pathways. Targeting these interactions might, thus, provide novel routes for rational drug design.