SH3domainbinding

SH3domainbinding refers to the interaction between SH3 domains and proline-rich motifs in target proteins, a key mechanism in intracellular signaling and cytoskeletal organization. The SH3 domain is a conserved ~60 amino acid module found in a wide range of proteins, including kinases, adaptors, and scaffolds.

Structure and binding: The SH3 domain folds into a compact beta-barrel formed by five beta-strands, with binding surfaces created by loop regions such as the RT loop and the n-Src loop. The binding pocket is a hydrophobic groove that recognizes polyproline sequences. Ligands typically present proline-rich motifs, often including PxxP cores, with flanking residues influencing specificity and affinity. Interactions are generally of moderate affinity, allowing rapid assembly and disassembly of signaling complexes.

Ligands and motifs: Common SH3 partners include cytoplasmic adaptors like Grb2, Crk, and Nck, which bind proline-rich motifs in signaling effectors such as SOS, WASP-family proteins, and dynamin. The exact consensus motifs vary; binding is influenced by motif orientation and surrounding sequence context.

Biological roles: SH3 domain binding mediates the assembly of signaling complexes at receptors and sites of endocytosis or actin remodeling. It contributes to pathway propagation, subcellular localization, and cross-talk between signaling cascades.

Regulation: Affinity and availability can be modulated by phosphorylation of the ligand, proline isomerization, or intramolecular interactions that mask SH3-binding surfaces. Cellular context and partner abundance determine network connectivity.

Clinical and research relevance: Disruption of SH3-mediated interactions is linked to cancer, neurological disorders, and immune dysfunction. Structural and biophysical studies, including crystallography, NMR, phage display, and binding assays, have elucidated the molecular basis of SH3 domain binding.