title: Solution structure of Grb2 reveals extensive flexibility necessary for target recognition.
abstract: Grb2 is an adaptor protein composed of a single SH2 domain flanked by two SH3 domains. Grb2 functions as an important evolutionary conserved link between a variety of cell membrane receptors and the Ras/MAP kinase-signaling cascade. Here, we describe the solution structure of Grb2 as revealed by NMR and small angle X-ray scattering measurements. We demonstrate that Grb2 is a flexible protein in which the C-terminal SH3 domain is connected to the SH2 domain via a flexible linker. This is in contrast to the previously described Grb2 crystal structure, which showed a compact structure with intramolecular contact between two SH3 domains. Binding experiments on Grb2 and peptides containing two different proline-rich sequences indicate that Grb2 adapts the relative position and orientation of the two SH3 domains to bind bivalently to the target peptide sequences.
authors.affiliation: Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Yuzawa
authors.forename: M
authors.initials: M
authors.lastname: Yokochi
authors.forename: H
authors.initials: H
authors.lastname: Hatanaka
authors.forename: K
authors.initials: K
authors.lastname: Ogura
authors.forename: M
authors.initials: M
authors.lastname: Kataoka
authors.forename: K
authors.initials: K
authors.lastname: Miura
authors.forename: V
authors.initials: V
authors.lastname: Mandiyan
authors.forename: J
authors.initials: J
authors.lastname: Schlessinger
authors.forename: F
authors.initials: F
authors.lastname: Inagaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D003198:Computer Simulation; D051380:GRB2 Adaptor Protein; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D018583:Pliability; D011392:Proline / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D012984:Software; D012996:Solutions; D013379:Substrate Specificity; D014961:X-Ray Diffraction; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D008024:Ligands; D011506:Proteins; D012996:Solutions; D011392:Proline