The Src homology 3 (SH3) domain is a small protein domain of about 60 amino-acid residues first identified as a conserved sequence in the non-catalytic part of several cytoplasmic protein tyrosine kinases (e.g. Src, Abl, Lck) [1]. Since then, it has been found in a great variety of other intracellular or membrane-associated proteins [2,3,4,5].

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 [6].

The function of the SH3 domain is not well understood. The current opinion is that they mediate assembly of specific protein complexes via binding to proline-rich peptides [7].

In general SH3 domains are found as single copies in a given protein, but there is a significant number of protein with two SH3 domains and a few with 3 or 4 copies.

So far, SH3 domains have been identified in the following proteins:

• Many vertebrate, invertebrate and retroviral cytoplasmic (non-receptor) protein tyrosine kinases. In particular in the Src, Abl, Bkt, Csk and ZAP70 families of kinases.
• Mammalian phosphatidylinositol-specific phospholipase C-γ-1 and -2.
• Mammalian phosphatidyl inositol 3-kinase regulatory p85 subunit.
• Mammalian Ras GTPase-activating protein (GAP).
• Adaptor proteins mediating binding of guanine nucleotide exchange factors to growth factor receptors: vertebrate GRB2, Caenorhabditis elegans sem-5 and Drosophila DRK. All of which have two SH3 domains.
• Mammalian Vav oncoprotein, a guanine nucleotide exchange factor of the CDC24 family.
• Some guanine-nucleotide releasing factors of the CDC25 family: yeast CDC25, yeast SCD25, fission yeast ste6.
• MAGUK proteins. These proteins consist of at least three types of domains: one or more copies of the DHR domain, a SH3 domain and a C-terminal guanylate kinase domain (see <PDOC00670>). Members of this family are: Drosophila lethal(1)discs large-1 tumor suppressor protein (gene Dlg1), mammalian tight junction protein ZO-1, vertebrate erythrocyte membrane protein p55, Caenorhabditis elegans protein lin-2, rat protein CASK and mammalian synaptic proteins SAP90/PSD-95, CHAPSYN-110/PSD-93, SAP97/DLG1 and SAP102.
• Plakin family of proteins, important actors in cross-linking force-bearing structures in the cell, contain a curious SH3 domain insertion in their chain of spectrin repeats [8].
• Miscellanous proteins interacting with vertebrate receptor protein tyrosine kinases: mammalian cytoplasmic protein Nck (3 copies), oncoprotein Crk (2 copies).
• Chicken Src substrate p80/85 protein (cortactin) and the similar human hemopoietic lineage cell specific protein Hs1.
• Mammalian dihydrouridine-sensitive L-type calcium channel β (regulatory) subunit including the related human myasthenic syndrome antigen B (MSYB).
• Mammalian neutrophil cytosolic activators of NADPH oxidase: p47 (NCF-1), p67 (NCF-2), and a potential homolog from Caenorhabditis elegans (B0303.7). NCF-1 and -2 have two copies of the SH3 domain, while B0303.7 has four.
• Some myosin heavy chains from amoebas, slime molds and yeast (gene MYO3).
• Mammalian palmitoyltransferase ZDHHC6 [9].
• Vertebrate and Drosophila spectrin and fodrin α-chain.
• Human amphiphysin.
• Yeast actin-binding protein ABP1.
• Yeast actin-binding protein SLA1 (3 copies).
• Yeast protein BEM1 and the fission yeast homolog scd2 (or ral3) (2 copies).
• Yeast BEM1-binding proteins BOI2 (BEB1) and BOB1 (BOI1).
• Yeast fusion protein FUS1.
• Yeast protein RSV167.
• Yeast protein SSU81.
• Yeast hypothetical proteins YAR014c (1 copy), YFR024c (1 copy), YHL002w (1 copy), YHR016c (1 copy), YJL020C (1 copy), YHR114w (2 copies) and the fission yeast homolog SpAC12C2.05c.
• Caenorhabditis elegans hypothetical protein F42H10.3.

The profile we developed covers the entire SH3 domain.