Interfacial water molecules in SH3 interactions: a revised paradigm for polyproline recognition

Abstract

In spite of its biomedical relevance, polyproline recognition is still not fully understood. The disagreement between the current description of SH3 complexes and their thermodynamic behavior calls for a revision of the SH3 binding paradigm. Recently, Abl-SH3 was demonstrated to recognize its ligands by a dual binding mechanism involving a robust network of water-mediated hydrogen bonds that complements the canonical hydrophobic interactions. The systematic analysis of the SH3 structural database presented here reveals that this dual binding mode is universal to SH3 domains. Tightly bound, buried interfacial water molecules were found in all SH3 complexes studied mediating the interaction between the peptide ligand and the domain. Moreover, structural waters were also identified in a high percentage of free SH3 domains. A detailed analysis of the pattern of water-mediated interactions enabled the identification of conserved hydration sites in the polyproline-recognition region and the establishment of relationships between hydration profiles and the sequence of both, ligands and SH3 domains. Water-mediated interactions were also systematically observed in WW, UEV and EVH-1 structures. These results clearly indicate that the current description of proline-rich sequence recognition by protein-protein interaction modules is incomplete and insufficient for a correct understanding of these systems. A new binding paradigm is required that includes interfacial water molecules as relevant elements in polyproline recognition.