A5008315680- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Streptococcal Infections and Treatments
- T-cell and B-cell Immunology
- Complement system in diseases
- Monoclonal and Polyclonal Antibodies Research
- Lipid Membrane Structure and Behavior
- Autoimmune and Inflammatory Disorders Research
- Bacteriophages and microbial interactions
- Erythrocyte Function and Pathophysiology
- Influenza Virus Research Studies
- Toxin Mechanisms and Immunotoxins
- vaccines and immunoinformatics approaches
- Acute Lymphoblastic Leukemia research
- ATP Synthase and ATPases Research
- Nanopore and Nanochannel Transport Studies
- Clostridium difficile and Clostridium perfringens research
- Galectins and Cancer Biology
- Escherichia coli research studies
- Immune Response and Inflammation
- Toxoplasma gondii Research Studies
- Adolescent and Pediatric Healthcare
- Antimicrobial Resistance in Staphylococcus
- Herpesvirus Infections and Treatments
- RNA modifications and cancer
Monash University
2015-2025
Australian Regenerative Medicine Institute
2015-2025
ARC Centre of Excellence in Advanced Molecular Imaging
2014-2023
Discovery Institute
2022
Australian Research Council
2007-2015
In-Q-Tel
2008
Peter MacCallum Cancer Centre
2007
University of Nottingham
2007
The University of Melbourne
2004-2005
Institute of Crystallography
2005
Proteins containing membrane attack complex/perforin (MACPF) domains play important roles in vertebrate immunity, embryonic development, and neural-cell migration. In vertebrates, the ninth component of complement perforin form oligomeric pores that lyse bacteria kill virus-infected cells, respectively. However, mechanism MACPF function is unknown. We determined crystal structure a bacterial protein, Plu-MACPF from Photorhabdus luminescens , to 2.0 angstrom resolution. The domain reveals...
Many bacterial pathogens utilize a type III secretion system to deliver multiple effector proteins into host cells. Here we found that the effectors, NleE from enteropathogenic E. coli (EPEC) and OspZ Shigella, blocked translocation of p65 subunit transcription factor, NF-κB, cell nucleus. NF-κB inhibition by was associated with decreased IL-8 expression in EPEC-infected intestinal epithelial Ectopically expressed also nuclear c-Rel, but not p50 or STAT1/2. homologues other attaching...
Membrane attack complex/perforin/cholesterol-dependent cytolysin (MACPF/CDC) proteins constitute a major superfamily of pore-forming that act as bacterial virulence factors and effectors in immune defence. Upon binding to the membrane, they convert from soluble monomeric form oligomeric, membrane-inserted pores. Using real-time atomic force microscopy (AFM), electron (EM), structure fitting, we have mapped assembly pathways CDC unprecedented detail accuracy, focussing on suilysin...
The pore-forming protein perforin is critical for defense against many human pathogens and preventing a catastrophic collapse of immune homeostasis, manifested in infancy as Type 2 familial hemophagocytic lymphohistiocytosis (FHL). However, no evidence has yet linked defective cytotoxicity with cancer susceptibility humans. Here, we examined function every patient reported the literature who lived to at least 10 years age without developing FHL despite inheriting mutations both their (PRF1)...
Abstract The membrane attack complex (MAC)/perforin-like protein complement component 9 (C9) is the major of MAC, a multi-protein that forms pores in target pathogens. In contrast to homologous proteins such as perforin and cholesterol-dependent cytolysins (CDCs), all which require for oligomerisation, C9 assembles directly onto nascent MAC from solution. However, molecular mechanism assembly remains be understood. Here we present 8 Å cryo-EM structure soluble form poly-C9 MAC. These data...
Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures both components (the...
Abstract Macrophage-expressed gene 1 (MPEG1/Perforin-2) is a perforin-like protein that functions within the phagolysosome to damage engulfed microbes. MPEG1 thought form pores in target membranes, however, its mode of action remains unknown. We use cryo-Electron Microscopy (cryo-EM) determine 2.4 Å structure hexadecameric assembly displays expected features soluble prepore complex. further discover prepore-like assemblies can be induced perforate membranes through acidification, such as...
The CD3εγ heterodimer is essential for expression and function of the T cell receptor. crystal structure human described to 2.1-Å resolution complexed with OKT3, a therapeutic mAb that not only activates tolerizes mature cells but also induces regulatory cells. mode dimerization provides general structural basis CD3 assembly maps candidate antigen receptor docking sites, including duplicated linear region rich in acidic residues unique CD3ε. OKT3 binds an atypically small area CD3ε has low...
HLA-G is a nonclassical major histocompatibility complex class I (MHC-I) molecule that primarily expressed at the fetal–maternal interface, where it thought to play role in protecting fetus from maternal immune response. binds limited repertoire of peptides and interacts with inhibitory leukocyte Ig-like receptors LIR-1 LIR-2 possibly certain natural killer cell receptors. To gain further insights into function, we determined 1.9-Å structure monomeric complexed endogenous peptide ligand...
Abstract Complement component 9 (C9) functions as the pore-forming of Membrane Attack Complex (MAC). During MAC assembly, multiple copies C9 are sequentially recruited to membrane associated C5b8 form a pore. Here we determined 2.2 Å crystal structure monomeric murine and 3.9 resolution cryo EM in polymeric assembly. Comparison with other proteins reveals that first transmembrane region (TMH1) is uniquely positioned inhibit its self-assembly absence C5b8. We further show following...
Significance Here, we present the structure of pore-forming toxin stonustoxin (SNTX), lethal factor in stonefish venom. Our work shows that SNTX comprises two homologous subunits (α and β), each which belongs to perforin superfamily immune effectors. In SNTX, α- β-Membrane Attack Complex-Perforin/Cholesterol-Dependent Cytolysin (MACPF/CDC) domains interact form a prepore-like complex. These data provide, our knowledge, first high-resolution insights into how MACPF/CDCs with one another...
Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered function as a series of “independent pegs” that either anchor the peptide (p) MHC-I and/or interact with spectrum αβ-T-cell receptors (TCRs) specific for pMHC-I epitope in question. Mining extensive structural database established many self- and viral peptides show direct interresidue interactions, an unexpected finding has led us idea “constrained”...
Abstract Background The pore-forming protein perforin is central to the granule-exocytosis pathway used by cytotoxic lymphocytes kill abnormal cells. Although this mechanism of killing conserved in bony vertebrates, cells are present other chordates and invertebrates, their has not been elucidated. In order understand evolution pathway, here we characterize origins perforin. Results We identified orthologs homologs human all but one species analysed from Euteleostomi, evidence for an earlier...