title: Order and disorder in large multi-site docking proteins of the Gab family--implications for signalling complex formation and inhibitor design strategies.
abstract: Large multi-site docking (LMD) proteins of the Gab, IRS, FRS, DOK and Cas families consist of one or two folded N-terminal domains, followed by a predominantly disordered C-terminal extension. Their primary function is to provide a docking platform for signalling molecules (including PI3K, PLC, Grb2, Crk, RasGAP, SHP2) in intracellular signal transmission from activated cell-surface receptors, to which they become coupled. A detailed analysis of the structural nature and intrinsic disorder propensity of LMD proteins, with Gab proteins as specific examples, is presented. By primary sequence analysis and literature review the varying levels of disorder and hidden order are predicted, revealing properties and a physical architecture that help to explain their biological function and characteristics, common for network hub proteins. The virulence factor, CagA, from Helicobacter pylori is able to mimic Gab function once injected by this human pathogen into stomach epithelial cells. Its predicted differential structure is compared to Gab1 with respect to its functional mimicry. Lastly, we discuss how LMD proteins, in particular Gab1 and Gab2, and their protein partners, such as SH2 and SH3 domain-containing adaptors like Grb2, might qualify for future anti-cancer strategies in developing protein-protein interaction (PPI) inhibitors towards binary interactors consisting of an intrinsically disordered epitope and a structured domain surface.
authors.affiliation: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK. philip.simister@imm.ox.ac.uk
authors.forename: Philip C
authors.initials: PC
authors.lastname: Simister
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Feller
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017510:Protein Folding; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D046912:Multiprotein Complexes