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Department of Biochemistry


Structural biology of cellular signalling by Toll/Interleukin 1 transmembrane receptors

Our group studies how microbial pathogens such as bacteria and viruses are recognized by the pattern recognition receptors (PRRs) of the innate immune system and the signaling responses that are generated. We are especially interested in the Toll-like receptors (TLRs). The microbial molecules or PAMPs that are recognized by TLRs can be divided broadly into two groups, microbial lipids such as lipopolysaccharide (LPS) and non-self nucleic acids from bacteria, viruses and other pathogenic microorganisms. These PAMPs bind and activate TLRs by promoting the dimerization of two receptor ectodomains and this in turn causes the cytosolic Toll/IL1 domains (TIR) to associate, creating a signal induced scaffold for the assembly of a postreceptor complex. TLRs function not only in immune system cells such as macrophages and dendritic cells but also at many other sites that require immune surveillance such intestinal mucosae and airway epithelia.

We study the molecular mechanisms of signal transduction by theTLRs using the methods of biophysics, structural biology, single molecule imaging, molecular genetics and cell biology.

Lab members: Dan Levy, Yang Yang,  Alkisti Alveropoulou-Malli, Istvan Foldi, Martyn Symmons, Anthony Dossang, Monique Gangloff, Miranda Lewis, Ardi Liaunardy-Jopeace, Martin Moncrieffe, Rui Wang, Olaniyi Opaleye, Brett Verstak, Samer Halibi, Irina Ogay, Lee Hopkins

Recent publications:

1.         Lewis, M., Arnot, C.J., Beeston, H., McCoy, A., Ashcroft, A.E., Gay, N.J. & Gangloff, M. Cytokine Spatzle binds to the Drosophila immunoreceptor Toll with a neurotrophin-like specificity and couples receptor activation. Proceedings of the National Academy of Sciences of the United States of America 110, 20461-6 (2013).

2.         Verstak, B., Arnot, C.J. & Gay, N.J. An Alanine-to-Proline Mutation in the BB-Loop of TLR3 Toll/IL-1R Domain Switches Signalling Adaptor Specificity from TRIF to MyD88. Journal of immunology 191, 6101-9 (2013).

3.         Gangloff, M., Arnot, C.J., Lewis, M. & Gay, N.J. Functional insights from the crystal structure of the N-terminal domain of the prototypical toll receptor. Structure 21, 143-53 (2013).

4.         Gangloff, M., Moreno, A. & Gay, N.J. Liesegang-like patterns of Toll crystals grown in gel. Journal of applied crystallography 46, 337-345 (2013).

5.         McIlroy, G., Foldi, I., Aurikko, J., Wentzell, J.S., Lim, M.A., Fenton, J.C., Gay, N.J. & Hidalgo, A. Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nature neuroscience 16, 1248-56 (2013).

6.         Weimann, L., Ganzinger, K.A., McColl, J., Irvine, K.L., Davis, S.J., Gay, N.J., Bryant, C.E. & Klenerman, D. A quantitative comparison of single-dye tracking analysis tools using Monte Carlo simulations. PloS one 8, e64287 (2013).

7.         Herre, J., Gronlund, H., Brooks, H., Hopkins, L., Waggoner, L., Murton, B., Gangloff, M., Opaleye, O., Chilvers, E.R., Fitzgerald, K., Gay, N., Monie, T. & Bryant, C. Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands. Journal of immunology 191, 1529-35 (2013).

8.         Moncrieffe, M.C., Fernandez, M.J., Spiteller, D., Matsumura, H., Gay, N.J., Luisi, B.F. & Leadlay, P.F. Structure of the glycosyltransferase EryCIII in complex with its activating P450 homologue EryCII. Journal of molecular biology 415, 92-101 (2012).

9.         Ve, T., Gay, N.J., Mansell, A., Kobe, B. & Kellie, S. Adaptors in Toll-Like Receptor Signaling and their Potential as Therapeutic Targets. Current drug targets 13, 1360-74 (2012).