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

This is the first Virtual School Seminar of 2020


Speaker Biosketch

Bostjan Kobe, Professor and Australian Laureate Fellow
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane

Bostjan Kobe is Professor of Structural Biology and Australian Laureate Fellow at the School of Chemistry and Molecular Biosciences, University of Queensland. He received his BSc in chemistry at the University of Ljubljana, Slovenia, and his PhD in biochemistry and biophysics at the University of Texas Southwestern Medical Center at Dallas, USA. His laboratory focuses on applying structural biology approaches to understanding 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 and the ARC Laureate Fellowship in 2018. He was the President of the SCANZ and a member of the ARC College of Experts.


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 (1). 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TLR adaptor MAL (2) and the TLR4:MAL complex by cryo-electron microscopy, and of MyD88 by micro-electron diffraction (unpublished). 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 (3). Crystal structures of human SARM TIR domain and grapevine NLR Run1 TIR domain 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 (4). The structures will be useful for therapeutic development against neurodegenerative and inflammatory diseases and for development of improved resistance in agricultural crops.

1. Ve et al (2015) Structure and function of Toll/interleukin-1 receptor/resistance protein (TIR) domains, Apoptosis, 20, 250 

2. Ve et al (2017) Structural basis of TIR-domain assembly formation in MyD88/MAL-dependent TLR4 signaling, Nat Struct Mol Biol 24, 743

3. Horsefield et al (2019). NAD(+) cleavage activity by animal and plant TIR domains in cell death pathways. Science 365, 793

4. Vajjhala et al (2017). The molecular mechanisms of signaling by cooperative assembly formation in innate immunity pathways. Mol Immunol 86, 23