Sandbox Reserved 1124: Difference between revisions
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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.<ref name="polyprolin"/> | 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.<ref name="polyprolin"/> | ||
It was first discovered that Grb2 binds to EGFR. Then, eight successive studies showed that Grb2 makes the connection between EGFR and | It was first discovered that Grb2 binds to EGFR. Then, eight successive studies showed that Grb2 makes the connection between EGFR and SOS, partly thanks to its SH3 domains. This discoveries enabled for a part to reveal that the subcellular location of signalling proteins plays an important role in the regulation of their function. SOS1 attaches to the plasma membrane after having been activated by Grb2, thus coming closer to Ras to activate it.<ref>PMID: 21686117</ref> | ||
== Gene expression == | == Gene expression == | ||
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== Structure == | == Structure == | ||
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 | 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.<ref name="anaïs"/> | ||
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==== 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> 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 C-Terminal SH3 domain has to recognize a 13 residues sequence with the following motif: P-x-x-x-R-x-x-K-P. | <scene name='71/719865/C-terminal_sh3_domains/1'>The C-terminal SH3 domain</scene> 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 C-Terminal 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. <ref name="polyprolin"/> | ||
In the Ras pathway, the Ct SH3 domain improves the overall stability of the Grb2-SOS complex.<ref >PMID:9383403</ref> | In the Ras pathway, the Ct SH3 domain improves the overall stability of the Grb2-SOS complex.<ref >PMID:9383403</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 interactions. Nevertheless, the proline-rich peptides can still bind to SH3 domains.<ref >PMID: 7716522</ref> And when the SH2 domain of Grb2 binds to a receptor, the ability of the SH3 domains to interact with | 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 interactions. Nevertheless, the proline-rich peptides can still bind to SH3 domains.<ref >PMID: 7716522</ref> And when the SH2 domain of Grb2 binds to a receptor, the ability of the SH3 domains to interact with SOS motifs does not change. <ref> The Biochemistry of Cell Signalling, Ernst J. M. Helmreich, 2001, p.52 [https://global.oup.com/academic/product/the-biochemistry-of-cell-signalling-9780198508205?cc=fr&lang=en&]</ref> | ||
== Functions and interactions with substrates == | == Functions and interactions with substrates == | ||
