Sandbox Reserved 1124: Difference between revisions
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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>. It has no catalytic domain. | 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>. It has no catalytic 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). 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). 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 two SH3 domains bind proline-rich regions of other proteins and enable the interaction with the Sos protein (guanine nucleotide exchange factor). The N-Terminal SH3 domain plays the main role in this interaction, it binds a proline-rich motif PxxP of the Ct domain of Sos. The Ct SH3 domain improves the overall stability of the Grb2-Sos complex. 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. | The two SH3 domains bind proline-rich regions of other proteins and enable the interaction with the Sos protein (guanine nucleotide exchange factor). The N-Terminal SH3 domain plays the main role in this interaction, it binds a proline-rich motif PxxP of the Ct domain of Sos. This binding region in Sos has the shape of a Polyprolin II helix. The Ct SH3 domain improves the overall stability of the Grb2-Sos complex. 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. | ||
===The SH2 domain=== | ===The SH2 domain=== | ||
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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 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. | |||
