Sandbox Reserved 1124: Difference between revisions
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Grb2 (Growth factor receptor-bound protein 2) is a connector protein that link grow factor receptors to the Ras signalling pathway. This protein implied in signal transduction pathways is essential for multiple cellular functions such as: embryonic development and cell proliferation. Grb2 can be found in the cytosol, the nucleus and the plasmic membrane. | Grb2 (Growth factor receptor-bound protein 2) is a connector protein that link grow factor receptors to the Ras signalling pathway. This protein implied in signal transduction pathways is essential for multiple cellular functions such as: embryonic development and cell proliferation. Grb2 can be found in the cytosol, the nucleus and the plasmic membrane. | ||
== History == | |||
The relevance of Grb2 has been enlightened thanks to studies on Caenorhabditis elegans. Sem-5, an homologue of Grb2, was found to be implied in the Let-60 pathway, an homologue of Ras. | |||
== DNA/RNA == | == DNA/RNA == | ||
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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).<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. | ||
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.<ref name="a">DOI:10.1038/nsb1294-898</ref> 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.<ref >DOI: http://dx.doi.org/10.1016/1074-5521(95)90080-2</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). 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.<ref name="a">DOI:10.1038/nsb1294-898</ref> 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.<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> The determination of the crystallographic structure enabled the observation of the junction between the SH3 and SH2 domains. It allows the two adjacent faces of the SH3 domains to be closer. This association is strenghtened by Van der Waals interaction. Nevertheless, the proline-rich peptides can still bind to SH3 domains. | 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> The determination of the crystallographic structure enabled the observation of the junction between the SH3 and SH2 domains. It allows the two adjacent faces of the SH3 domains to be closer. This association is strenghtened by Van der Waals interaction. Nevertheless, the proline-rich peptides can still bind to SH3 domains. | ||
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=== The C-terminal SH3 domain=== | === The C-terminal SH3 domain=== | ||
The Ct 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. | |||
<scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domains</scene> …. | |||
==Function== | ==Function== | ||
