Sandbox Reserved 1124: Difference between revisions

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This domain is very essential to the function of Grb2. In fact, <scene name='71/719865/Sh2domains/1'>the SH2 domain</scene> 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.<ref name="polyprolin"/>
This domain is very essential to the function of Grb2. In fact, <scene name='71/719865/Sh2domains/1'>the SH2 domain</scene> 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.<ref name="polyprolin"/>


The central SH2 domain binds growth factor receptors (EGFR or PDGFR) or scaffold proteins. 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> SH2 interacts preferentially with a tyrosine phosphorylated sequence with the following motif: pY-X-N-X (X is a hydrophobic residue).<ref > DOI:10.1371/journal.pone.0074482</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.<ref name="A"/>
The central SH2 domain binds growth factor receptors (EGFR or PDGFR) or scaffold proteins. 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> SH2 interacts preferentially with a tyrosine phosphorylated sequence with the following motif: pY-x-N-x (x is a hydrophobic residue).<ref > DOI:10.1371/journal.pone.0074482</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.<ref name="A"/>


The SH2 domain 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>]]
The SH2 domain 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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<scene name='71/719865/Sh3_domain_1/1'>The N-terminal SH3 domain</scene> goes from the amino acid 1 to 56, it 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">PMID: 7773779</ref> and this binding region in SOS has the shape of a Polyprolin II helix. <ref name="polyprolin">PMID: 11314042</ref>
<scene name='71/719865/Sh3_domain_1/1'>The N-terminal SH3 domain</scene> goes from the amino acid 1 to 56, it plays the main role in the interaction with the SOS protein. It binds a proline-rich motif P-x-x-P of the C-Terminal domain of SOS<ref name="a">PMID: 7773779</ref> and this binding region in SOS has the shape of a Polyprolin II helix. <ref name="polyprolin">PMID: 11314042</ref>
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 (<scene name='71/719865/Glu2-ala5/1'>Glu2-Ala5</scene>), S2 (<scene name='71/719865/Ile24-lys26/1'>Ile24-Lys26</scene>) and S6 (<scene name='71/719865/Ile53-met55/1'>Ile53-Met55</scene>). The second sheet contains the strands S3 (<scene name='71/719865/Val27-asn29/1'>Val27-Asn29</scene>), S4 (<scene name='71/719865/Trp36-leu41/1'>Trp36-Leu41</scene>) and S5 (<scene name='71/719865/Asp45-ile48/1'>Asp45-Ile48</scene>). 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 (<scene name='71/719865/Glu2-ala5/1'>Glu2-Ala5</scene>), S2 (<scene name='71/719865/Ile24-lys26/1'>Ile24-Lys26</scene>) and S6 (<scene name='71/719865/Ile53-met55/1'>Ile53-Met55</scene>). The second sheet contains the strands S3 (<scene name='71/719865/Val27-asn29/1'>Val27-Asn29</scene>), S4 (<scene name='71/719865/Trp36-leu41/1'>Trp36-Leu41</scene>) and S5 (<scene name='71/719865/Asp45-ile48/1'>Asp45-Ile48</scene>). 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"/>


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