Click on the picture for structural details.
The SH3 (Src Homology 3) domain is a small conserved sequence of about 60 amino acid residues that interacts with proline-rich peptides to form protein aggregates.
Structurally, the SH3 domain folds as a compact beta-barrel of five to six anti-parallel beta-strands. The hydrophobic beta-strands are connected by hydrophilic loops to form two orthogonal beta-sheets bringing the amino and the carboxyl termini of the domain close to each other. The ligands of the SH3 domains are peptides containing a ten residue consensus sequence, XPXXPPPFXP (where X is any amino acid residue, F is phenylalanine and P is peoline). This peptide forms a left-handed polyproline (PPII) helix that lies along the binding site of the SH3 domain, with its prolines interacting with the aromatic residues on the hyrophobic face of the SH3 domain.
Functionally, the SH3 domain is involved in cell-cell communication and signal transduction from the cell surface to the nucleus. It acts as part of an adapter molecule and recruits downstream proteins in a signalling pathway. For example, in the eye development pathway in Drosophila (Sevenless Pathway), a ligand from the R8 cell, Boss (Bride of Sevenless), binds two molecules of Sev (Sevenless) receptors on the surface of the R7 cell. This binding dimerizes the receptors which are Protein Tyrosine Kinases, so now they are close to one another and can transphosphorylate each other. There is a conformational change in the Tyr kinase domain of the receptor as a result of this phosphorylation which recruits a protein called Grb2 (and its homologs) near the cell membrane. Grb2 has two domains: SH2 and SH3. the SH2 domain binds a specific phospho-tyrosine of the receptor and SH3 domain binds and recruits Sos, a GTP Exchange Factor (GEF), to the membrane. Sos is activated by this membrane localization. Sos activates Ras, a small G-protein, by an exchange of its GDP to GTP. Then, the signal is transduced from Ras to the nucleus by a protein kinase cascade. As a result, there is an activation of a transcription factor in the nucleus by its phosphorylation and transcription of specific proteins leading to cellular differentiation and specialization in the R7 cell. Furthermore, the SH3 domain can regulate the activity of a protein by intramolecular interactions. For example, the SH3 domain of Src binds a proline-rich region of itself to downregulate its own activity by forming a closed, inactive conformation. The loss of this binding, as a result of different mutations, can lead to a constitutively active Src molecule and cancer.