title: Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase.
abstract: Receptor protein-tyrosine kinases, through phosphorylation of specific tyrosine residues, generate high-affinity binding sites which direct assembly of multienzyme signalling complexes. Many of these signalling proteins, including phospholipase C gamma, GTPase-activating protein and phosphatidylinositol-3-OH kinase, contain src-homology 2 (SH2) domains, which bind with high affinity and specificity to tyrosine-phosphorylated sequences. The critical role played by SH2 domains in signalling has been highlighted by recent studies showing that mutation of specific phosphorylation sites on the platelet-derived growth factor receptor impair its association with phosphatidylinositol-3-OH kinase, preventing growth factor-induced mitogenesis. Here we report the solution structure of an isolated SH2 domain from the 85K regulatory subunit of phosphatidylinositol-3-OH kinase, determined using multidimensional nuclear magnetic resonance spectroscopy. The structure is characterized by a central region of beta-sheet flanked by two alpha-helices, with a highly flexible loop close to functionally important residues previously identified by site-directed mutagenesis.
authors.affiliation: Department of Biochemistry, University of Oxford, UK.
authors.forename: G W
authors.initials: GW
authors.lastname: Booker
authors.forename: A L
authors.initials: AL
authors.lastname: Breeze
authors.forename: A K
authors.initials: AK
authors.lastname: Downing
authors.forename: G
authors.initials: G
authors.lastname: Panayotou
authors.forename: I
authors.initials: I
authors.lastname: Gout
authors.forename: M D
authors.initials: MD
authors.lastname: Waterfield
authors.forename: I D
authors.initials: ID
authors.lastname: Campbell
mesh_terms: D000818:Animals; D002417:Cattle; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases; D010716:Phosphatidylinositols / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism* / Q000648:ultrastructure*; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D010716:Phosphatidylinositols; D011994:Recombinant Proteins; D010770:Phosphotransferases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases