SH3 domain

Peptide binding

The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner. Classical SH3 domains are restricted in humans to intracellular proteins, although the small human MIA family of extracellular proteins also contain a domain with an SH3-like fold.

Many SH3-binding epitopes of proteins have a consensus sequence that can be represented as a regular expression or Short linear motif:

-X-P-p-X-P- 1 2 3 4 5

with 1 and 4 being aliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the hydrophobic pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.

SH3 interactomes

SH3 domain-mediated protein-protein interaction networks, i.e., SH3 interactomes, revealed that worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis. Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.

Proteins with SH3 domain

• Signal transducing adaptor proteins
• CDC24
• Cdc25
• PI3 kinase
• Phospholipase
• Ras GTPase-activating protein
• Vav proto-oncogene
• GRB2
• p54 S6 kinase 2 (S6K2)
• SH3D21
• ARMH3 (potentially)
• STAC3
• Some myosins
• SH3 and multiple ankyrin repeat domains: SHANK1, SHANK2, SHANK3
• YAP1
• ARHGAP12
• vexin (VXN)
• TANGO1
• Integrase
• Focal Adhesion Kinase (FAK, PTK2)
• Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta)
• TRIP10 (cip4)