SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [ PUBMED:15335710 PUBMED:11256992 ]. They are found in a great variety of intracellular or membrane-associated proteins [ expand

SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [ PUBMED:15335710 PUBMED:11256992 ]. They are found in a great variety of intracellular or membrane-associated proteins [ PUBMED:1639195 PUBMED:14731533 PUBMED:7531822 ] for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.

The SH3 domain has a characteristic fold which consists of five or six β-strands arranged as two tightly packed anti-parallel β-sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [ PUBMED:7953536 ].

The crystal structure of the SH3 domain of the cytoskeletal protein spectrin, and the solution structures of SH3 domains of phospholipase C (PLC-y) and phosphatidylinositol 3-kinase p85 alpha-subunit, have been determined [ PUBMED:1279434 PUBMED:7684655 PUBMED:7681365 ]. In spite of relatively limited sequence similarity, their overall structures are similar. The domains belong to the α+β structural class, with five to eight β-strands forming 2 tightly-packed, anti-parallel β-sheets arranged in a barrel-like structure, and intervening loops sometimes forming helices. Conserved aliphatic and aromatic residues form a hydrophobic core (A11, L23, A29, V34, W42, L52 and V59 in PLC-y [ PUBMED:7681365 ]) and a hydrophobic pocket on the molecular surface (L12, F13, W53 and P55 in PLC-y). The conserved core is believed to stabilise the fold, while the pocket is thought to serve as a binding site for target proteins. Conserved carboxylic amino acids located in the loops, on the periphery of the pocket (D14 and E22), may be involved in protein-protein interactions via proline-rich regions. The N- and C-terminal are packed in close proximity, indicating that they are independent structural modules.