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Grb2 is a small protein of 217 residues with a molecular mass of about 25,206 Da and composed of three remarkable domains : a single SH2 (Src Homology 2) domain (60 to 152 pdb) flanked by two conserved SH3 domains (respectively 1 to 58 and 156 to 215 pdb)<ref name="A">Gagani Athauda, Donald P Bottaro Atlas of Genetics and Cytogenetics in Oncology and Haematology (2007)[http://atlasgeneticsoncology.org/Genes/GRB2ID386ch17q25.html]</ref>. The two SH3 domains bind proline-rich regions of other proteins and enable the interaction with the Sos protein (Son of Sevenless, guanine nucleotide exchange factor). Moreover it has no catalytic domain. The Grb2 protein can exist in two states : monomeric or dimeric. However, only the monomeric Grb2 conformation is able to bind SOS protein and regulate MAP kinases. In this case, the dimeric Grb2 plays the role of an inhibitor. In fact, the dimer dissociation allows the phosphorylation of Grb2 160 tyrosine and the bond of SH2 domain with phosphorylated tyrosines. To conclude, the switch between these two conformations controls the MAP kinase activity.

'''The SH2 domain'''

The amino acid in red are residues which are responsible for forming the phosphopeptide binding pocket. In green, this is residues which can bind to the negatively charged phosphorylated tyrosine residue of the binding peptide. This domain is very essential for the function of Grb2. Actually, several mutations in the SH2 domains can cause human diseases. A mutation for example of the arginin residue at position 5 of βB can cancel the phosphotyrosine dependent interactions.<ref name="Kousik"/>

The SH2 domain of Grb2 enables the interaction with receptors, scaffold proteins, tyrosine kinases but also with other adaptor proteins. Indeed, Shc is an intermediate between some receptors and Grb2.

<scene name='71/719865/Sh3_domain_1/1'>The N-terminal SH3 domain</scene> plays the main role in the interaction with the SOS protein. It binds a proline-rich motif PxxP of the C-Terminal domain of SOS<ref name="a">DOI:10.1038/nsb1294-898</ref> and this binding region in SOS has the shape of a Polyprolin II helix.  

The N-terminal SH3 domain encompasses two three-stranded antiparallel β-sheets, one strand crosses the two sheets. This confers a barrel-like structure upon the domain. The first sheet contains the 3 following strands: S1 (Glu2-Ala5), S2 (Ile24-Lys26) and S6 (Ile53-Met55). The second sheet contains the strands S3 (Val27-Asn29), S4 (Trp36-Leu41) and S5 (Asp45-Ile48). The structure of this SH3 domain is stabilized by a high number of hydrophobic residues, which form the centre of the protein.<ref name="a"/>

'''The C-terminal SH3 domain'''