SH3

SH3 stands for Src Homology 3, a small, highly conserved protein domain found in many signaling proteins. It is typically about 60 amino acids in length and adopts a compact beta-barrel fold that presents a ligand-binding groove.

SH3 domains recognize proline-rich sequences, most often forming polyproline type II helices. They bind to peptides containing PxxP motifs, with binding influenced by the orientation of the motif and nearby residues. Interactions are usually of modest affinity on their own but can be strengthened through multivalent engagement in signaling complexes.

Functionally, SH3 domains act as modular interaction modules that recruit and assemble signaling networks. They are common in Src family kinases and adaptor proteins such as Grb2 and Crk, as well as effector proteins like members of the WASP family, linking signals to cytoskeletal dynamics and other downstream processes.

Regulation of SH3-mediated interactions can occur through intramolecular or intermolecular mechanisms. In some proteins, SH3 domains participate in autoinhibitory interactions that keep signaling activity in check until appropriate cues relieve the constraint. Ligand binding and phosphorylation can modulate affinity and specificity, shaping signaling outcomes.

Clinical and research relevance centers on their role in diverse pathways, including growth signaling and immune responses. Because SH3 domains mediate protein-protein interactions rather than catalytic activity, they have been explored as targets to disrupt pathogenic signaling networks in disease contexts.