A5031635513- Biochemical effects in animals
- Sirtuins and Resveratrol in Medicine
- Vitamin C and Antioxidants Research
- Calcium signaling and nucleotide metabolism
- Endoplasmic Reticulum Stress and Disease
- Signaling Pathways in Disease
- Immune Response and Inflammation
- Enzyme Structure and Function
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Crystallization and Solubility Studies
- Influenza Virus Research Studies
- Protein Structure and Dynamics
- X-ray Diffraction in Crystallography
- interferon and immune responses
- Advanced Electron Microscopy Techniques and Applications
- Cytomegalovirus and herpesvirus research
- Toxin Mechanisms and Immunotoxins
- GDF15 and Related Biomarkers
- Microbial Natural Products and Biosynthesis
- ATP Synthase and ATPases Research
- Advanced Glycation End Products research
- Mechanisms of cancer metastasis
- Lung Cancer Treatments and Mutations
- Advanced Data Storage Technologies
- Parkinson's Disease Mechanisms and Treatments
The University of Queensland
2019-2025
Griffith University
2023
Stockholm University
2023
Queens University
2021
AgriBio
2021
NAD depletion as pathogen response One way that plants respond to infection is by sacrificing the infected cells. The nucleotide-binding leucine-rich repeat immune receptors responsible for this hypersensitive carry Toll/interleukin-1 receptor (TIR) domains. In two papers, Horsefield et al. and Wan report these TIR domains cleave metabolic cofactor nicotinamide adenine dinucleotide (NAD + ) part of their cell-death signaling in pathogens. Similar links mammalian TIR-containing proteins...
Cyclic adenosine diphosphate (ADP)–ribose (cADPR) isomers are signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via nicotinamide adenine dinucleotide (oxidized form) (NAD + ) hydrolysis. We show that v-cADPR (2′cADPR) v2-cADPR (3′cADPR) cyclized O-glycosidic bond formation between the ribose moieties in ADPR. Structures of 2′cADPR-producing TIR reveal conformational changes lead to an active assembly resembles those Toll-like adaptor domains....
The NADase SARM1 (sterile alpha and TIR motif containing 1) is a key executioner of axon degeneration therapeutic target for several neurodegenerative conditions. We show that potent inhibitor undergoes base exchange with the nicotinamide moiety adenine dinucleotide (NAD
Innate immunity relies on Toll-like receptors (TLRs) to detect pathogen-associated molecular patterns. The TIR (Toll/interleukin-1 receptor) domain-containing TLR adaptors TRIF (TIR adaptor-inducing interferon-β) and TRAM (TRIF-related adaptor molecule) are essential for MyD88-independent signaling. However, the structural basis of domain-based signaling remains unclear. Here, we present cryo-EM structures filaments formed by domains at resolutions 3.3 Å 5.6 Å, respectively. Both reveal...
Thoeris defense systems protect bacteria from infection by phages via abortive infection. In these systems, ThsB proteins serve as sensors of and generate signaling nucleotides that activate ThsA effectors. Silent information regulator SMF/DprA-LOG (SIR2-SLOG) containing effectors are activated cyclic ADP-ribose (ADPR) isomers 2'cADPR 3'cADPR, triggering nicotinamide adenine dinucleotide (NAD
Axon loss underlies symptom onset and progression in many neurodegenerative disorders. degeneration injury disease is promoted by activation of the NAD-consuming enzyme SARM1. Here, we report a novel activator SARM1, metabolite pesticide neurotoxin vacor. Removal SARM1 completely rescues mouse neurons from vacor-induced neuron axon death vitro vivo. We present crystal structure Drosophila regulatory domain complexed with this activator, vacor VMN, which as most potent yet known likely to...
Eukaryotic TIR (Toll/interleukin-1 receptor protein) domains signal via TIR–TIR interactions, either by self-association or interaction with other domains. In mammals, are found in Toll-like receptors (TLRs) and cytoplasmic adaptor proteins involved pro-inflammatory signaling. Previous work revealed that the MAL domain (MAL ) nucleates assembly of MyD88 into crystalline arrays vitro . A microcrystal electron diffraction (MicroED) structure has previously been solved, revealing a two-stranded...
Abstract Axon loss underlies symptom onset and progression in many neurodegenerative disorders. degeneration injury disease is promoted by activation of the nicotinamide adenine dinucleotide (NAD)-consuming enzyme SARM1 (sterile alpha TIR motif-containing protein 1). Here, we report vacor mononucleotide (VMN), a metabolite pesticide neurotoxin vacor, as most potent yet activator. Removal shows complete rescue from vacor-induced neuron axon death vitro vivo . We present crystal structure VMN...
The Toll/interleukin-1 receptor (TIR) domains are key innate immune signalling modules. Here, we present the crystal structure of TIR domain human interleukin-1 10 (IL-1R10), also called interleukin 1 accessory protein like 2. It is similar to that IL-1R9 (IL-1RAPL1) but shows significant structural differences those from Toll-like receptors (TLRs) and adaptor proteins MyD88 adaptor-like (MAL) MyD88. Interactions in their respective crystals higher-order assemblies (MAL MyD88) reveal...
Abstract Cyclic ADP ribose (cADPR) isomers are important signaling molecules produced by bacterial and plant Toll/interleukin-1 receptor (TIR) domains via NAD + hydrolysis, yet their chemical structures unknown. We show that v-cADPR (2’cADPR) v2-cADPR (3’cADPR) cyclized O -glycosidic bond formation between the moieties in ADPR. Structures of (2’cADPR)-producing TIR reveal conformational changes required for active assembly resembles those Toll-like adaptor domains, mutagenesis data...
The crystal structure determination of the armadillo repeat motif (ARM) domain Drosophila SARM1 (dSARM1 ARM ) is described, which required combination a number sources phase information in order to obtain interpretable electron-density maps. central executioner programmed axon degeneration, common feature early many neurodegenerative diseases. held inactive state healthy axons by its N-terminal auto-inhibitory domain, and activated cleave NAD upon injury, triggering subsequent degeneration....
Abstract We describe the crystal structure determination of ARM domain Drosophila SARM1 (dSARM1 ), which required combination a number sources phase information in order to obtain interpretable electron density maps. is central executioner process axon degeneration, common feature early range neurodegenerative diseases. held inactive state healthy axons by its N-terminal auto-inhibitory domain, and activated cleave NAD + upon injury, triggering subsequent degeneration. To characterize...
Abstract SARM1 is an inducible NAD + hydrolase that the central executioner of pathological axon loss. Recently, we elucidated molecular mechanism activation, demonstrating a metabolic sensor regulated by levels and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to allosteric site within N-terminal ARM domain. In healthy neurons with abundant , blocks access NMN this site. However, injury or disease biosynthetic enzyme NMNAT2 drop, increasing NMN/ ratio...
CUB-domain containing protein-1 (CDCP1) is a heavily glycosylated transmembrane protein that highly expressed in many epithelial cancers such as breast, ovarian, cervical, prostate, and urothelial cancers.Our laboratory previously identified an antibody, 10D7 has high specificity affinity for the ectodomain of CDCP1 with KD 0.28 nM.10D7 effective at delivering payloads PET scan detection cytotoxin treatment animal models cancer, justifying clinical trials cancer patients including our own...
Wallerian degeneration is a conserved program of injury-induced axon degeneration, and analogous to the blockage transport that characterises early stages many neurodegenerative diseases.In recent years, TLR adaptor SARM1 has been well characterised as initiator degeneration.SARM1 intrinsic NADase activity through dimerization TIR domains, this essential for degeneration.However, molecular details pathway downstream are not understood.Axundead (Axed) regulator in Drosophila, with loss...