Wellcome Trust Career Development Fellow
Structural and Functional Studies of the NOD-like Receptor Family
I gained my PhD in Molecular Virology from the University of Cambridge in 2002 having characterised the dimerisation initiation site (DIS) of the retrovirus HTLV-1 and identified the DIS in the ovine lentivirus Maedi Visna. In recognition of this work I was awarded the International Retrovirology Young Investigator Award for the UK in 2001. I then moved to Imperial College London and studied the role of the cellular proteins PTB and EBP1 in the initiation of translation by positive strand RNA viruses such as FMDV. As part of this work I solved the crystal structure of EBP1 and proved that PTB existed as a monomer in solution, not a dimer as had been previously assumed.
I returned to Cambridge in 2006 and switched fields to begin studying the nature of the innate immune response. In 2008 I was awarded a Wellcome Trust Career Development Fellowship with which to investigate the structure and function of the NOD like receptors NOD1 and NOD2. During this Fellowship my group have made significant progress in developing our understanding of the evolutionary basis of NOD1 and NOD2 function; the mechanisms of signal transduction and interaction with the adaptor protein RIP2; and in elucidating the nature of the interaction between NOD2 and its ligand muramyl dipeptide.
Subject groups/Research projects
Understanding the innate immune system is essential for the development of new therapies for the treatment of microbial infection, the management of autoimmune disorders and the provision of protective immunity via vaccination. My group investigates two members of the intracellular NOD-like receptor family, NOD1 and NOD2. These proteins are activated by fragments of bacterial peptidoglycan; γ-D-glutamyl-meso-diaminopimelic acid for NOD1 and muramyl dipeptide for NOD2.
Ligand recognition stimulates receptor oligomerisation and initiates a signalling cascade that ultimately leads to the upregulation of a pro-inflammatory immune response. NOD1 and NOD2 are both associated with a predisposition to inflammatory disorders. The best characterised of these is the role of NOD2 single nucleotide polymorphisms in the inflammatory bowel disorder Crohn’s Disease.
Our work is specifically aimed at developing an understanding of how these proteins recognise their ligands and how they propagate signalling within the cell. We are investigating the evolutionary and molecular basis of protein-protein interactions particularly between NOD1 and NOD2 and their protein cofactors and adaptor proteins. We are also looking at the impact of polymorphisms on the function of the receptors. To achieve these aims we are using a variety of functional assays and biochemical and biophysical techniques. We hope to ultimately utilise x-ray crystallography to determine the molecular structure of these proteins.
Collaborators outside this directory
- Professor N Gay - http://www.bioc.cam.ac.uk/people/uto/gay
- Man SM , Tourlomousis P, Hopkins L, Monie T, Fitzgerald K, Bryant C (2013) Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate interleukin-1Β production. (J Immunol. 2013 Nov 15; 191(10):5239-46. )
- Parkhouse R, Ebong I-O, Robinson CV, Monie TP*. The N-terminal region of the human autophagy protein ATG16L1 contains a domain that folds into a helical structure consistent with formation of a coiled-coil. (PLoS One. 2013 Sep 24;8(9):e76237 ) *Corresponding author
- Boyle J, Mayle S, Parkhouse R and Monie TP* (2013). Comparative genomic and sequence analysis provides insight into the molecular functionality of NOD1 and NOD2. Front. Immunol. 4:317. doi: 10.3389/fimmu.2013.00317 *Corresponding author
- Herre J, Gronlund H, Brookes H, Waggoner L, Gooch S, Murton B, Opaleye N, Fitzgerald K, Gay N, Monie TP*, Bryant C*(2013). Allergens as Immuno-Modulatory Proteins: the cat dander protein FelD1 enhances Toll-like receptor activation by lipid ligands. J Immunol. Aug 15;191(4):1529-35 *Joint corresponding authors.
- Joseph P Boyle, Clare E Bryant and Tom P Monie* (2013). Cell Swelling and the NLRP3 Inflammasome. Immunity. Mar 21;38(3):399.*Corresponding author
- Monie TP*. (2013) NLR activation takes a direct route. Trends Biochem Sci. 2013 Mar;38(3):131-9 *Corresponding author
- Yereddi NR, Cusdin FS, Namadurai S, Packman LC, Monie TP, Slayny P, Clare JJ, Powel AJ, Jackson AP. (2013) The immunoglobulin domain of the sodium channel b3-subunit contains a surface-localized disulfide bond that is required for homophilic binding. FASEB J. Feb;27(2):568-80