PROSITE documentation PDOC50002
Src homology 3 (SH3) domain profile


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.

Last update:

October 2017 / Text and profile revised.


Technical section

PROSITE method (with tools and information) covered by this documentation:

SH3, PS50002; Src homology 3 (SH3) domain profile  (MATRIX)


1AuthorsMayer B.J. Hamaguchi M. Hanafusa H.
TitleA novel viral oncogene with structural similarity to phospholipase C.
SourceNature 332:272-275(1988).
PubMed ID2450282

2AuthorsMusacchio A. Gibson T. Lehto V.P. Saraste M.
TitleSH3--an abundant protein domain in search of a function.
SourceFEBS Lett. 307:55-61(1992).
PubMed ID1639195

3AuthorsPawson T. Schlessingert J.
TitleSH2 and SH3 domains.
SourceCurr. Biol. 3:434-442(1993).
PubMed ID15335710

4AuthorsMayer B.J. Baltimore D.
TitleSignalling through SH2 and SH3 domains.
SourceTrends Cell Biol. 3:8-13(1993).
PubMed ID14731533

5AuthorsPawson T.
TitleProtein modules and signalling networks.
SourceNature 373:573-580(1995).
PubMed ID7531822

6AuthorsKuriyan J. Cowburn D.
SourceCurr. Opin. Struct. Biol. 3:828-837(1993).

7AuthorsMorton C.J. Campbell I.D.
TitleSH3 domains. Molecular 'Velcro'.
SourceCurr. Biol. 4:615-617(1994).
PubMed ID7953536

8AuthorsDaday C. Kolsek K. Graeter F.
TitleThe mechano-sensing role of the unique SH3 insertion in plakin domains revealed by Molecular Dynamics simulations.
SourceSci. Rep. 7:11669-11669(2017).
PubMed ID28916774

9AuthorsAbrami L. Dallavilla T. Sandoz P.A. Demir M. Kunz B. Savoglidis G. Hatzimanikatis V. van der Goot F.G.
TitleIdentification and dynamics of the human ZDHHC16-ZDHHC6 palmitoylation cascade.
SourceElife 6:0-0(2017).
PubMed ID28826475

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