A5011005127- Cell death mechanisms and regulation
- Hippo pathway signaling and YAP/TAZ
- interferon and immune responses
- Parkinson's Disease Mechanisms and Treatments
- Chronic Lymphocytic Leukemia Research
- Neuroscience and Neural Engineering
- Neurological disorders and treatments
- PARP inhibition in cancer therapy
- Bacillus and Francisella bacterial research
- Redox biology and oxidative stress
- Research on Leishmaniasis Studies
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Phagocytosis and Immune Regulation
- Viral Infectious Diseases and Gene Expression in Insects
- Legume Nitrogen Fixing Symbiosis
- Insect Resistance and Genetics
- Metal-Catalyzed Oxygenation Mechanisms
- Nuclear Structure and Function
- Reproductive tract infections research
- SARS-CoV-2 and COVID-19 Research
- Viral Infections and Immunology Research
- Endoplasmic Reticulum Stress and Disease
- Porphyrin Metabolism and Disorders
- RNA regulation and disease
Walter and Eliza Hall Institute of Medical Research
2021-2023
The University of Melbourne
2021-2022
University of Canterbury
2020
Phosphorylation of the MLKL pseudokinase by RIPK3 kinase leads to oligomerization, translocation to, and permeabilization of, plasma membrane induce necroptotic cell death. The precise choreography activation remains incompletely understood. Here, we report Monobodies, synthetic binding proteins, that bind domain within human cells their crystal structures in complex with domain. While Monobody-32 constitutively binds hinge region, Monobody-27 via an epitope overlaps site is only exposed...
Abstract The ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, dysregulation necroptosis inflammatory diseases has led to widespread interest targeting pathway therapeutically. This mode is executed by terminal effector, MLKL pseudokinase, which licensed kill following phosphorylation its upstream regulator, RIPK3 kinase. precise molecular details underlying activation are still emerging and, intriguingly, appear mechanistically-diverge between...
Background & AimsNecroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims controversial. A comprehensive, fundamental understanding pathways involved liver disease critically underpins rational strategies for therapeutic intervention. We sought to define role and relevance necroptosis pathology.MethodsSeveral animal models human...
Abstract Necroptosis is a caspase-independent, pro-inflammatory mode of programmed cell death which relies on the activation terminal effector, MLKL, by upstream protein kinase RIPK3. To mediate necroptosis, RIPK3 must stably interact with, and phosphorylate pseudokinase domain although precise molecular cues that provoke necroptotic signaling are incompletely understood. The recent finding S227 phosphorylation occurrence stable RIPK3:MLKL complex in human cells prior to exposure necroptosis...
Abstract The necroptosis pathway is a lytic, pro-inflammatory mode of cell death that widely implicated in human disease, including renal, pulmonary, gut and skin inflammatory pathologies. precise mechanism the terminal steps pathway, where RIPK3 kinase phosphorylates triggers conformation change oligomerization effector, MLKL, are only emerging. Here, we structurally identify RIPK3-mediated phosphorylation MLKL activation loop as cue for pseudokinase domain dimerization. dimerization...
Across the globe, 2-3% of humans carry p.Ser132Pro single nucleotide polymorphism in MLKL, terminal effector protein inflammatory form programmed cell death, necroptosis. Here we show that this substitution confers a gain necroptotic function human cells, with more rapid accumulation activated MLKLS132P biological membranes and overriding pharmacological endogenous inhibition MLKL. In mouse equivalent Mlkl S131P mutation gene dosage dependent reduction sensitivity to TNF-induced necroptosis...
Necroptosis is a lytic and pro-inflammatory form of programmed cell death executed by the terminal effector, MLKL (mixed lineage kinase domain-like) pseudokinase. Downstream Toll-like receptor stimulation, trafficked to plasma membrane via Golgi-, actin- microtubule-machinery, where activated accumulates until critical threshold exceeded ensues. Mechanistically, MLKL's function relies on disengagement N-terminal membrane-permeabilising four-helix bundle domain from central autoinhibitory...
During aerobic growth, the Gram-positive facultative anaerobe and opportunistic human pathogen Streptococcus pneumoniae generates large amounts of hydrogen peroxide that can accumulate to millimolar concentrations. The mechanism by which this catalase-negative bacterium withstand endogenous is incompletely understood. enzyme alkylhydroperoxidase D (AhpD) has been shown contribute pneumococcal virulence oxidative stress responses in vivo We demonstrate here SpAhpD exhibits weak...
While humans lack the biosynthetic pathways for meso-diaminopimelate and l-lysine, they are essential bacterial survival therefore attractive targets antibiotics. It was recently discovered that members of Chlamydia family utilize a rare aminotransferase route l-lysine pathway, thus offering new enzymatic drug target. Here we characterize diaminopimelate from Verrucomicrobium spinosum (VsDapL), nonpathogenic model bacterium trachomatis. Complementation experiments verify V. dapL gene encodes...
ABSTRACT Across the globe, 2-3% of humans carry p.Ser132Pro single nucleotide polymorphism in MLKL , terminal effector protein inflammatory form programmed cell death, necroptosis. We show that this substitution confers a gain necroptotic function human cells, with more rapid accumulation activated S132P biological membranes and overriding pharmacological endogenous inhibition MLKL. In mouse equivalent Mlkl S131P mutation gene dosage dependent reduction sensitivity to TNF-induced necroptosis...