Sandbox Reserved 1124: Difference between revisions

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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 (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. 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.

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. 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. 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===

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 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 (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. 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.
+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. 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. 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===