Poster
Yun Shi
Griffith University
Southport, Queensland, Australia
Biswa Mishra
Griffith University
Southport, Queensland, Australia
Premraj Rajaratnam
Griffith University
Southport, Queensland, Australia
Veronika Masic
Griffith University
Southport, Queensland, Australia
Tamim Mosaiab
Griffith University
Southport, Queensland, Australia
Mohammad K. Manik
The University of Queensland
Brisbane, Queensland, Australia
Sulin Li
The University of Queensland
Brisbane, Queensland, Australia
Jeffrey Nanson
The University of Queensland
Brisbane, Queensland, Australia
Weixi Gu
The University of Queensland
Brisbane, Queensland, Australia
Bostjan Kobe
The University of Queensland
Brisbane, Queensland, Australia
Thomas Ve
Griffith University
Southport, Queensland, Australia
The Toll/interleukin-1 receptor (TIR) domain is found in plant, mammalian and bacterial immune systems [1]. It was first described as a protein-protein interaction module mediating signalling downstream of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) families in animals. However, studies of plant immune receptors, the neurodegenerative disease therapeutic target SARM1, and many bacterial TIR domain-containing proteins revealed that TIR domains have enzymatic activities [2] and can produce diverse signaling molecules using nicotinamide adenine dinucleotide (NAD+) as a substrate. We have characterized TIR domain proteins and their enzymatic products using an integrative approach combining NMR, chemistry, cryoEM and crystallography. Our results have revealed mechanisms of NAD+ cleavage and inhibition [3-4], novel NAD+ metabolites/analogs [5-6] as well as insight into their interaction with downstream immune receptors.
[1] Li et al (2023) Curr Opin Microbiology 74, 102316
[2] Horsefield et al (2019) Science 365, 793
[3] Figley et al (2021) Neuron 79, 1118
[4] Shi et al (2022) Mol Cell 82, 1643
[5] Manik et al (2022) Science, eadc8969
[6] Shi et al (2024) Sci Adv, eadn3310