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13:00-14:00, Tuesday, January 7, 2020


Speaker:Nicholas John GAY, Ph.D.

Department of Biochemistry

University of Cambridge

Topic: Cooperativity and complexity in the regulation of inflammatory signalling

Host: Feng Shao, Ph.D.

Abstract

Toll like receptors (TLRs) are pivotal in triggering the innate immune response to pathogen infection. Ligand binding to leucine rich repeats on the receptor induces the dimerization of both receptor ectodomain and the cytosolic Toll/interleukin-1 receptor (TIR) domain, providing a nucleation signal for assembly of an oligomeric scaffold, the Myddosome, leading to inflammatory signalling. Myeloid differentiation primary response 88 (MyD88) is required by all TLRs except TLR3 and signalling is thought to proceed via a mechanism that involves the stepwise, sequential assembly of individual components. Recent studies in our lab find that the death domains of human MyD88 spontaneously and reversibly associate to form helical filaments in vitro. A 3.1 Å cryo-EM structure reveals that the architecture of the filament is identical to that of the MyD88-IRAK4-IRAK2 heterooligomeric Myddosome. Additionally, the death domain of IRAK4 interacts with the filaments to reconstitute the non-stoichiometric 6:4 MyD88-IRAK4 complex. Single molecule analysis in vivo shows that in the resting state MyD88 is present as short oligomers or monomers and that interaction with the activated receptor relieves autoinhibition allowing the rapid assembly of the closed Myddosome complex. Together, these data suggest that the MyD88 scaffold may be preformed or rapidly assembled on receptor activation and TIR engagement.

Professor Nicholas John GAY will also present new studies of B-cell adaptor protein (BCAP), a multimodular, multifunctional signal transducer that regulates signal transduction pathways in leukocytes, including macrophages, B cells, and T cells. BCAP suppresses inflammatory signaling by Toll-like receptors (TLRs) and we elucidate patterns of phosphorlyation and adaptor binding that underlie this regulation.

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