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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.
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 SH2 domain'''
The central SH2 domain binds growth factor receptors (EGFR or PDGFR) or scaffold proteins. It interacts preferentially with a tyrosine phosphorylated sequence with the following motif: pY-X-N-X (X is a hydrophobic residue).<ref > Wikipedia Grb2 [https://en.wikipedia.org/wiki/GRB2]</ref>. Other non-receptor tyrosine kinases have also this motif and interact with Grb2 SH2 domain, such as BCR-Abl, focal adhesion kinase, insulin receptor substrate 1 and PTPN11.
The central SH2 domain binds growth factor receptors (EGFR or PDGFR) or scaffold proteins. It interacts preferentially with a tyrosine phosphorylated sequence with the following motif: pY-X-N-X (X is a hydrophobic residue).<ref > Wikipedia Grb2 [https://en.wikipedia.org/wiki/GRB2]</ref>. Other non-receptor tyrosine kinases have also this motif and interact with Grb2 SH2 domain, such as BCR-Abl, focal adhesion kinase, insulin receptor substrate 1 and PTPN11.
<scene name='71/719865/Sh2domains/1'>The SH2 domain</scene> encompasses 8 beta strands (<scene name='71/719865/Beta_strand_61-64/1'>61 to 64</scene> ; <scene name='71/719865/Beta_strand_82-87/1'>82 to 87</scene> ; <scene name='71/719865/Beta_strand_95-101/1'>95 to 101</scene> ; <scene name='71/719865/Beta_strand_104-112/1'>104 to 112</scene> ; <scene name='71/719865/Beta_strand_114-116/1'>114 to 116</scene> ; <scene name='71/719865/Beta_strand_118-122/1'>118 to 122</scene> ; <scene name='71/719865/Beta_strand_124-127/1'>124 to 127</scene> ; <scene name='71/719865/Beta_strand_149-152/2'>149 to 152</scene>) and 2 alpha helices (<scene name='71/719865/Alpha_helix_67-75/1'>67 to 75</scene> and <scene name='71/719865/Alpha_helix_128-134/1'>128 to 134</scene>)<ref> [http://www.uniprot.org/uniprot/P62993 UniProtKB P62993 Human]</ref>. The βB, βC and βD strands compose a three-stranded antiparallel β-sheet and the 2 α-helices are positioned on both sides. Moreover, the short parallel βA and βG strands extend the central β-sheet. There are also βD', βE and βF strands which are smaller β-sheet-like structure. <ref>DOI:10.1007/s10858-008-9272-0</ref> [[Image:Sequence_of_the_SH2_domain_of_Grb2.PNG | thumb | upright=3 | Sequence of the SH2 domain (60 to 152 amino acids) of Grb2 <ref name="Kousik">Kousik Kundu In Silico Prediction of Modular Domain-Peptide Interactions (2015) [https://scholar.google.com/citations?view_op=view_citation&hl=en&user=0iOlQDAAAAAJ&citation_for_view=0iOlQDAAAAAJ:qUcmZB5y_30C]</ref>]]
<scene name='71/719865/Sh2domains/1'>The SH2 domain</scene> encompasses 8 beta strands (<scene name='71/719865/Beta_strand_61-64/1'>61 to 64</scene> ; <scene name='71/719865/Beta_strand_82-87/1'>82 to 87</scene> ; <scene name='71/719865/Beta_strand_95-101/1'>95 to 101</scene> ; <scene name='71/719865/Beta_strand_104-112/1'>104 to 112</scene> ; <scene name='71/719865/Beta_strand_114-116/1'>114 to 116</scene> ; <scene name='71/719865/Beta_strand_118-122/1'>118 to 122</scene> ; <scene name='71/719865/Beta_strand_124-127/1'>124 to 127</scene> ; <scene name='71/719865/Beta_strand_149-152/2'>149 to 152</scene>) and 2 alpha helices (<scene name='71/719865/Alpha_helix_67-75/1'>67 to 75</scene> and <scene name='71/719865/Alpha_helix_128-134/1'>128 to 134</scene>)<ref> [http://www.uniprot.org/uniprot/P62993 UniProtKB P62993 Human]</ref>. The βB, βC and βD strands compose a three-stranded antiparallel β-sheet and the 2 α-helices are positioned on both sides. Moreover, the short parallel βA and βG strands extend the central β-sheet. There are also βD', βE and βF strands which are smaller β-sheet-like structure. <ref>DOI:10.1007/s10858-008-9272-0</ref> [[Image:Sequence_of_the_SH2_domain_of_Grb2.PNG | thumb | upright=3 | Sequence of the SH2 domain (60 to 152 amino acids) of Grb2 <ref name="Kousik">Kousik Kundu In Silico Prediction of Modular Domain-Peptide Interactions (2015) [https://scholar.google.com/citations?view_op=view_citation&hl=en&user=0iOlQDAAAAAJ&citation_for_view=0iOlQDAAAAAJ:qUcmZB5y_30C]</ref>]]
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=== The N-Terminal SH3 domain===
'''The N-Terminal SH3 domain'''
<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 Ct domain of Sos.<ref name="a">DOI:10.1038/nsb1294-898</ref> This binding region in Sos has the shape of a Polyprolin II helix.  
<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 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===
'''The C-terminal SH3 domain'''
<scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domain</scene> improves the overall stability of the Grb2-Sos complex.<ref >DOI: http://dx.doi.org/10.1016/1074-5521(95)90080-2</ref>
<scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domain</scene> improves the overall stability of the Grb2-SOS complex.<ref >DOI: http://dx.doi.org/10.1016/1074-5521(95)90080-2</ref>
Moreover, this Ct domain specifically binds to proteins with a P-X-I/L/V-D/N-R-X-X-K-P motif such as Gab1.<ref>DOI:10.1016/S0960-9822(02)01038-2</ref>  
Moreover, this C-Terminal domain specifically binds to proteins with a P-X-I/L/V-D/N-R-X-X-K-P motif such as Gab1.<ref>DOI:10.1016/S0960-9822(02)01038-2</ref>  
The C-terminal SH3 domain goes from the amino acid 156 to 215. The role of this domain is little known. But it has been shown that, for a stable complex formation, the Ct SH3 domain has to recognize a 13 residues sequence with the following motif: P-x-x-x-R-x-x-K-P. Sos contains this sequence, as well as Gab1, which also binds to Grb2. The interaction of Grb2 with Gab1 has been demonstrated with precipitation experiments.  
The C-terminal SH3 domain goes from the amino acid 156 to 215. The role of this domain is little known. But it has been shown that, for a stable complex formation, the Ct SH3 domain has to recognize a 13 residues sequence with the following motif: P-x-x-x-R-x-x-K-P. Sos contains this sequence, as well as Gab1, which also binds to Grb2. The interaction of Grb2 with Gab1 has been demonstrated with precipitation experiments.  




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