Signalling by cooperative assembly formation (SCAF) by TIR domains in innate immunity and cell death pathways

TIR (Toll/interleukin-1 receptor, resistance protein) domains are key components of innate immunity and cell-death signaling pathways in animals and plants. Signaling depends on association of TIR domains. We have been able to reconstitute large assemblies of the TLR (Toll-like receptor) adaptor TIR domains and determined the structure of the filamentous assembly of TLR adaptor MAL by cryo-electron microscopy. As an unexpected twist, we found that the TIR domains involved in cell-death pathways, including those from the human TLR adaptor SARM1, involved in axon degeneration, and those from plant immune receptors (NLRs), possess self-association-dependent NAD+-cleavage activity. Crystal structures of human SARM TIR domain and grapevine NLR RUN1 TIR domains in complex with small-molecule ligands shed light on the structural basis of this enzymatic activity. Our studies unify the mechanism of function of TIR domains as "signaling by cooperative assembly formation (SCAF)" with prion-like features that leads to the activation of effector enzymes, and show that some TIR domains can themselves function as effector enzymes. The structures will be useful for therapeutic development against neurodegenerative and inflammatory diseases and for development of improved resistance in agricultural crops.

Professor Bostjan Kobe FAA

Professor Bostjan Kobe is Professor of Structural Biology and ARC Laureate Fellow at the School of Chemistry and Molecular Biosciences and affiliated with the Institute for Molecular Science at the University of Queensland. He received a BSc degree in chemistry at the University of Ljubljana, Slovenia, and a PhD degree at the University of Texas Southwestern Medical Center at Dallas, USA. His laboratory focuses on applying structural biology approaches to understanding proteins involved in infection and immunity. He received the 2001 Minister's Prize for Achievement in Life Sciences, an ARC Federation Fellowship in 2005, the 2009 ASBMB Roche Medal, the 2018 ASBMB Beckman Coulter Discovery Award, the ARC Laureate Fellowship in 2018 and became a Fellow of the Australian Academy of Science in 2018. He was the President of the SCANZ and a member of the ARC College of Experts. He has over 240 publications and over 15000 citations.

Seminar host: Professor Rob Parton (r.parton@imb.uq.edu.au)