Interfacial water molecules in SH3 interactions: Getting the full picture on polyproline recognition by protein-protein interaction domains

The recognition of proline-rich sequences by protein-protein interaction modules is essential for many cellular processes. Nonetheless, in spite of the wealth of structural and functional information collected over the last two decades, polyproline recognition is still not well understood. The patent inconsistency between the generally accepted description of SH3 interactions, based primarily on the stacking of hydrophobic surfaces, and their markedly exothermic character is a clear illustration of the higher complexity of these systems. Here we review the structural and thermodynamic evidence revealing the need for a revision of the current binding paradigm, incomplete and clearly insufficient for a full understanding of binding affinity and specificity, to include interfacial water molecules as universal and relevant elements in polyproline recognition.