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‘Molecular basis for activation and catalysis of the pro-neurodegenerative NADase SARM1’

Neuroscience & Non-Communicable Diseases Seminar Series

Speaker: Dr Thomas Ve, Research Leader, ARC Future Fellow and NHMRC Investigator at the Institute for Glycomics, Griffith University.

Bio:  Dr Thomas Ve is a Research Leader, ARC Future Fellow and NHMRC Investigator at the Institute for Glycomics, Griffith University. He received his MSc degree in Molecular Biology from the University of Bergen, Norway in 2006, and his PhD degree from the University of Queensland, under the supervision of Professor Bostjan Kobe in 2011. After his PhD he worked as a Postdoctoral Fellow at University of Queensland before joining Griffith University in 2015. Dr Ve’s group is using a multidisciplinary approach, combining X-ray crystallography, cryo-EM, NMR, and other biological, and biophysical techniques to characterise proteins and protein complexes to better understand signalling mechanisms in innate immunity and axon degeneration. He was a lead investigator in seminal structural studies that defined the molecular scripture for signal amplification in Toll-like receptor pathways and established the pro-neurodegenerative protein SARM1 as a NAD+ cleavage enzyme. Recently his team provided the molecular basis for how SARM1 is activated and catalyse the cleavage of NAD+.

Dr Ve has published over 40 papers in leading journals including in Science, Neuron, Cell Host Microbe, Nature Structural and Molecular Biology, Nature Communications and PNAS. In recognition of his contributions, Dr Ve has been awarded the Lorne Protein Young Investigator Award (2016), the COMBIO ECR Award (2016) and the Crystal 29 - Rising Star Award (2014). He has also received two Australian Research Council Fellowships (DECRA and Future Fellowship) and a National Health and Medical Research Council Investigator Grant. 

Abstract: Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD+)- cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD+, activates SARM1 via an unknown mechanism. Using crystallography, cryo-EM, NMR, biochemical and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD+ and show that both metabolites compete for binding to the autoinhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We show that NMN binding disrupts ARM-TIR interactions in the full-length SARM1 octamer, enabling its TIR domains to self-associate and form a catalytic site capable of cleaving NAD+. These structural insights identify SARM1 as a metabolic sensor of the NMN/NAD+ ratio, define the mechanism of SARM1 activation, and may enable a path to the development of allosteric inhibitors that block SARM1 activation.

Enquiries: Lindsay Wu

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Event Date: 
Friday, 18 June 2021 - 3:00pm
On line via Microsoft Teams meeting
Event Type: 
School of Medical Sciences (SoMS)
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