title: The structure of the inter-SH2 domain of class IA phosphoinositide 3-kinase determined by site-directed spin labeling EPR and homology modeling.
abstract: Phosphoinositide (PI) 3-kinases catalyze the phosphorylation of the D3 position of the inositol ring of PI, and its phosphorylated derivatives and play important roles in many intracellular signal transducing pathways. Class IA PI3-kinases contain distinct regulatory (p85) and catalytic (p110) subunits. p110 is stabilized and inhibited by constitutive association with p85, and is disinhibited when the SH2 domains of p85 bind to tyrosyl-phosphorylated proteins. Because the two subunits do not dissociate, disinhibition of p110 presumably occurs by an allosteric mechanism. To explore the means by which p85 regulates the activity of p110, structures of the inter-SH2 domain of p85 were determined with and without phosphopeptide by using a combination of site directed spin labeling EPR and homology modeling and molecular dynamics. The inter-SH2 domain is assigned as a rigid anti-parallel coiled-coil whose primary function is to bind p110, facilitating inhibition of p110 by the N-terminal SH2 domain of p85.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fu
authors.forename: Eliah
authors.initials: E
authors.lastname: Aronoff-Spencer
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Gerfen
mesh_terms: D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry* / Q000145:classification / Q000235:genetics / Q000378:metabolism; D021122:Protein Subunits; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D013113:Spin Labels; D013816:Thermodynamics; D018909:src Homology Domains
chemical_list: D021122:Protein Subunits; D011993:Recombinant Fusion Proteins; D013113:Spin Labels; D019869:Phosphatidylinositol 3-Kinases