Grb10 SH2 Domain: Difference between revisions
From Proteopedia
Jump to navigationJump to search
Jason Marks (talk | contribs) |
No edit summary |
||
| (5 intermediate revisions by 3 users not shown) | |||
| Line 1: | Line 1: | ||
<StructureSection load='1NRV' size='350' side='right' caption='Crystal Structure of the SH2 Domain of Grb10 (PDB entry [[ | <StructureSection load='1NRV' size='350' side='right' caption='Crystal Structure of the SH2 Domain of Grb10 (PDB entry [[1nrv]])' scene=''> | ||
==Introduction== | ==Introduction== | ||
Grb10 (Growth factor Receptor-Binding protein) is | '''Grb10 (Growth factor Receptor-Binding protein)''' is the member of a family of adapter proteins (Grb7 and Grb14) that interacts with tyrosine kinases. <ref name=Guan>PMID: 12551896 </ref> This protein acts as a growth suppressor by competitively binding to [[insulin receptors]] and IGF1R ([[Insulin-like growth factor 1 receptor]]) which prevents other hormones to bind and facilitate chemical reactions within the cell. It has also been found to interact with E3 Ubiquitin Ligase NEDD4 which promotes the degradation of IGF1R. New developments in the research of Grb10 have shown that by inhibiting the expression of this gene, mice express a phenotype that has an increase in body mass, improved glucose homeostasis, improved insulin sensitivity and reduced adiposity. Grb10 knockout mice have a 30% increase in muscle mass, which has designated it to be called the 'Hulk' protein. | ||
==Dimerization of the Grb10 SH2 Domain== | ==Dimerization of the Grb10 SH2 Domain== | ||
The crystal structure of Grb10 SH2 (Src Homology) domain (molecular mass = 12.4 kDa) was an important step to understanding how this protein interacts with IGF1 receptors, and although the SH2 domain functions as an independent segment, it forms a dimer in physiological environments. <ref name=Guan>PMID: 12551896 </ref> The <scene name='Grb10_SH2_Domain/Best_interface/ | The crystal structure of Grb10 SH2 (Src Homology) domain (molecular mass = 12.4 kDa) was an important step to understanding how this protein interacts with IGF1 receptors, and although the SH2 domain functions as an independent segment, it forms a dimer in physiological environments. <ref name=Guan>PMID: 12551896 </ref> The <scene name='Grb10_SH2_Domain/Best_interface/2'>dimer interface</scene> exists due to the middle hydrophobic Phe515 and uncharged Thr504 (labeled blue) residues packed into its equivalent counter parter on the other protomer, designated as Phe515' and Thr504' (labeled red); Gln511 (blue) forms a hydrogen bond to the backbone of Asp514' (red) while the side chain of Asn519 forms two hydrogen bonds to the backbone of Lys505'. <ref name=Guan>PMID: 12551896 </ref> The interface ends with Leu518 and Phe-496' via hydrophobic interactions. <ref name=Guan>PMID: 12551896 </ref>. The structure of Grb10 SH2 forms similar SH2 domains found in other proteins, which have an <scene name='Grb10_SH2_Domain/Alpha_helix/2'>alpha helix</scene> on the outsides with anti-parallel <scene name='Grb10_SH2_Domain/Beta_sheet/1'>beta sheets</scene>. | ||
To ensure the crystallographic structure of Grb10 SH2 is indeed a dimer in solution, Evan Stein and colleagues substituted Phe515 at the dimer interface with arginine (electrically charged side chain) and found, using gel filtration chromatography (Picture 1), that the Grb10 SH2 dimer had indeed become independent monomers. | To ensure the crystallographic structure of Grb10 SH2 is indeed a dimer in solution, Evan Stein and colleagues substituted Phe515 at the dimer interface with arginine (electrically charged side chain) and found, using gel filtration chromatography (Picture 1), that the Grb10 SH2 dimer had indeed become independent monomers. | ||
| Line 35: | Line 33: | ||
==Interaction Between Grb10 and E3 Ubiquitin Ligase NEDD4== | ==Interaction Between Grb10 and E3 Ubiquitin Ligase NEDD4== | ||
<Structure load='3M7F' size='350' frame='true' align='left' caption='Crystal structure of the Nedd4 C2/Grb10 SH2 complex PDB entry [[ | <Structure load='3M7F' size='350' frame='true' align='left' caption='Crystal structure of the Nedd4 C2/Grb10 SH2 complex PDB entry [[3m7f]])' scene='Insert optional scene name here' /> | ||
Grb10 has now been shown to not only inhibit insulin receptors and IGF1R kinase activity, but also interacts via its SH2 domain with the C2 domain of E3 ubiquitin ligase NEDD4 facilitating ubiquitation of IGF1R <ref>PMID: 20980250</ref>. It is hypothesized that the Grb10 SH2 interaction with the E3 domain of NEDD4 may allow NEDD4 to come in close proximity to IGF1R promoting degradation.<ref>PMID: 20980250</ref> | Grb10 has now been shown to not only inhibit insulin receptors and IGF1R kinase activity, but also interacts via its SH2 domain with the C2 domain of E3 ubiquitin ligase NEDD4 facilitating ubiquitation of IGF1R <ref>PMID: 20980250</ref>. It is hypothesized that the Grb10 SH2 interaction with the E3 domain of NEDD4 may allow NEDD4 to come in close proximity to IGF1R promoting degradation.<ref>PMID: 20980250</ref> | ||
