SH3domain

The SH3 domain, or Src Homology 3 domain, is a small protein interaction module found in a wide range of eukaryotic proteins, including Src family kinases and numerous adaptor and scaffold proteins. It mediates specific, low-to-moderate affinity interactions with proline-rich ligands, enabling the assembly of signaling complexes and coordination of cellular processes such as cytoskeletal organization and endocytosis.

Structurally, the SH3 domain is a compact beta-barrel composed of about 60 amino acids arranged into five or six antiparallel beta-strands. The ligand-binding surface is formed by loops, including the RT and n-Src loops, which recognize short proline-rich motifs. SH3 domains often occur in tandem or in combination with other modular domains, allowing more complex or higher-avidity interactions.

Binding and specificity are centered on proline-rich sequences, commonly containing PxxP motifs. SH3 domains typically recognize particular orientations and surrounding residues, yielding class I and class II ligand preferences in many cases. Affinity is generally moderate, and binding can be modulated by intramolecular interactions within the host protein or by regulatory phosphorylation events that alter domain accessibility or conformation.

Biological roles of SH3 domains include recruiting kinases, phosphatases, and structural proteins to signaling complexes, shaping pathways related to growth, differentiation, and cytoskeletal dynamics. Prominent SH3-containing proteins include Src, Grb2, Crk, Nck, and SH3BP2, among others. In research, SH3 domains serve as models of modular protein-protein interaction domains and as tools for studying signaling networks; they are also explored as targets to disrupt specific protein interactions in disease contexts.