The innate immune pathway, namely the Toll receptor and downstream signaling molecules, was relatively recently identified. This family of receptors was originally found and characterized in Drosophila, but so far ten different Toll-like receptors have been found in human. The role of this pathway in adult human health has been found to have implications on both neurodegeneration and stroke. Despite the central role of the Toll-like receptor in initiating the innate immune response, the molecular and biophysical nature of the protein-protein interactions mediating this signal remain poorly understood. The broad aims of this project are to better understand the innate immune pathway at a molecular level. Specifically, this research proposal is focused on the adaptor molecule MyD88, a universal adaptor that binds to all ten Toll-like receptors. The specific questions to be asked for each aim are: 1) what is the interaction interface between Toll/Interleukin-1 receptor domains and what critical amino acids mediate this interaction? This will be addressed by using X-ray crystallography to solve the crystal structure for MyD88 and point mutagenesis for confirmation of specific interacting amino acids. 2) Is the association of MyD88 with all ten Toll-like receptors of equal magnitude or does it differ? Analytical ultracentrifugation will be utilized to determine the binding constants of each Toll/Interleukin-1 receptor domain with Myd88.
| Lasker, Michael V; Nair, Satish K (2006) Intracellular TLR signaling: a structural perspective on human disease. J Immunol 177:11-6 |
| Lasker, Michael V; Kuruvilla, Santosh M; Gajjar, Mark M et al. (2006) Metal ion-mediated reduction in surface entropy improves diffraction quality of crystals of the IRAK-4 death domain. J Biomol Tech 17:114-21 |
| Lasker, Michael V; Gajjar, Mark M; Nair, Satish K (2005) Cutting edge: molecular structure of the IL-1R-associated kinase-4 death domain and its implications for TLR signaling. J Immunol 175:4175-9 |
