A5020208790- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- Protein Degradation and Inhibitors
- Histone Deacetylase Inhibitors Research
- Cancer-related gene regulation
- RNA modifications and cancer
- SARS-CoV-2 and COVID-19 Research
- Signaling Pathways in Disease
- Peptidase Inhibition and Analysis
- Protein Structure and Dynamics
- Ubiquitin and proteasome pathways
- RNA Research and Splicing
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- COVID-19 Clinical Research Studies
- Polyamine Metabolism and Applications
- Bacterial Genetics and Biotechnology
- Mass Spectrometry Techniques and Applications
- interferon and immune responses
- DNA and Nucleic Acid Chemistry
- Immune responses and vaccinations
- RNA and protein synthesis mechanisms
- Advanced Electron Microscopy Techniques and Applications
- Bacteriophages and microbial interactions
- DNA Repair Mechanisms
The University of Sydney
2016-2025
UNSW Sydney
2009-2015
University of California, Los Angeles
2015
Metagenomics was used to characterize viral genomes in clinical specimens of horses with various organ-specific diseases unknown aetiology. A novel parvovirus as well a previously described hepacivirus closely related human hepatitis C virus and equid herpesvirus 2 were identified the cerebrospinal fluid neurological signs. Four co-infecting picobirnaviruses, including an unusual genome fused RNA segments, divergent anellovirus found plasma two febrile horses. cyclovirus characterized from...
The COVID-19 pandemic, caused by SARS-CoV-2, has led to substantial morbidity, mortality, and disruption globally. Cellular entry of SARS-CoV-2 is mediated the viral spike protein, affinity ligands this surface protein have potential for applications as antivirals diagnostic reagents. Here, we describe selection cyclic peptide receptor binding domain (RBD) from three distinct libraries (in excess a trillion molecules each) mRNA display. We identified six high with dissociation constants (KD)...
Global control of COVID-19 requires broadly accessible vaccines that are effective against SARS-CoV-2 variants. In this report, we exploit the immunostimulatory properties bacille Calmette-Guérin (BCG), existing tuberculosis vaccine, to deliver a vaccination regimen with potent SARS-CoV-2-specific protective immunity. Combination BCG stabilised, trimeric form spike antigen promoted rapid development virus-specific IgG antibodies in blood vaccinated mice, was further augmented by addition...
Significant recent advances in structural biology, particularly the field of cryoelectron microscopy, have dramatically expanded our ability to create models proteins and protein complexes. However, many remain refractory these approaches because their low abundance, stability, or-in case complexes-simply not having yet been analyzed. Here, we demonstrate power using cross-linking mass spectrometry (XL-MS) for high-throughput experimental assessment structures This included those produced by...
Although ACE2 is the primary receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a systematic assessment of host factors that regulate binding to SARS-CoV-2 spike protein has not been described. Here, we use whole-genome CRISPR activation identify controlling cellular interactions with SARS-CoV-2. Our top hit was TLR-related cell surface called leucine-rich repeat-containing 15 (LRRC15). LRRC15 expression sufficient promote where they form complex. mRNA...
Chloroplast genes encoding photosynthesis-associated proteins are predominantly transcribed by the plastid-encoded RNA polymerase (PEP). PEP is a multi-subunit complex composed of subunits similar to bacterial polymerases (RNAPs) stably bound set nuclear-encoded PEP-associated (PAPs). PAPs essential activity and chloroplast biogenesis, but their roles poorly defined. Here, we present cryoelectron microscopy (cryo-EM) structures native 21-subunit transcription elongation from white mustard...
Abstract Chromatin remodellers hydrolyse ATP to move nucleosomal DNA against histone octamers. The mechanism, however, is only partially resolved, and it unclear if conserved among the four remodeller families. Here we use single-molecule assays examine mechanism of action CHD4, which part least well understood family. We demonstrate that binding energy for CHD4-nucleosome complex formation—even in absence nucleotide—triggers significant conformational changes at entry side, effectively...
Chromodomain Helicase DNA-binding protein 4 (CHD4) is a chromatin-remodeling enzyme that has been reported to regulate DNA-damage responses through its N-terminal region in poly(ADP-ribose) polymerase-dependent manner. We have identified and determined the structure of stable domain (CHD4-N) this region. The-fold consists four-α-helix bundle with structural similarity high mobility group box, well known as DNA binding module. show CHD4-N binds higher affinity than DNA. also CHD4, although...
The nucleosome remodelling and deacetylase (NuRD) complex is essential for the development of animals. NuRD has roles in regulating gene expression repairing damaged DNA. comprises at least six proteins with two or more paralogues each protein routinely identified when purified from cell extracts. To understand structure function NuRD, a map direct subunit interactions needed. Dozens published studies have attempted to define inter-subunit connectivities. We propose that conclusions reported...
Some epigenetic modifications are inherited from one generation to the next, providing a potential mechanism for inheritance of environmentally acquired traits. Transgenerational RNAi phenotypes in Caenorhabditis elegans provides an excellent model study this phenomenon, and although studies have implicated both chromatin small RNA pathways heritable silencing, their relative contributions remain unclear. Here, we demonstrate that putative histone methyltransferases SET-25 SET-32 required...
Members of the bromodomain and extra-terminal domain (BET) family proteins (bromodomain-containing (BRD) 2, 3, 4, T) are widely expressed highly conserved regulators gene expression in eukaryotes. These have been intimately linked to human disease, more than a dozen clinical trials currently underway test BET-protein inhibitors as modulators cancer. However, although it is clear that these use their bromodomains bind both histones transcription factors bearing acetylated lysine residues,...
Chromatin structure and function is regulated by reader proteins recognizing histone modifications and/or variants. We recently identified that PWWP2A tightly binds to H2A.Z-containing nucleosomes involved in mitotic progression cranial-facial development. Here, using vitro assays, we show distinct domains of mediate binding free linker DNA as well H3K36me3 nucleosomes. In vivo, strongly recognizes regulatory regions weakly H3K36me3-containing gene bodies. Further, an MTA1-specific...
The nucleosome remodeling and deacetylase (NuRD) complex is essential for metazoan development but has been refractory to biochemical analysis. We present an integrated analysis of the native mammalian NuRD complex, combining quantitative mass spectrometry, cross-linking, protein biochemistry, electron microscopy define architecture complex. built from a 2:2:4 (MTA, HDAC, RBBP) module 1:1:1 (MBD, GATAD2, Chromodomain-Helicase-DNA-binding [CHD]) module, displays considerable structural...
Cyclic peptide library screening technologies show immense promise for identifying drug leads and chemical probes challenging targets. However, the structural functional diversity encoded within such libraries is largely undefined. We have systematically profiled affinity, selectivity, features of library-derived cyclic peptides selected to recognize three closely related targets: acetyllysine-binding bromodomain proteins BRD2, -3, -4. report affinities as low 100 pM specificities up...
Recent research has implicated arginine methylation as a major regulator of cellular processes, including transcription, translation, nucleocytoplasmic transport, signalling, DNA repair, RNA processing and splicing. Arginine is evolutionarily conserved, it now thought that may rival other post-translational modifications such phosphorylation in terms its occurrence the proteome. In addition, multiple recent examples demonstrate an exciting new theme: interplay between phosphorylation. this...
Significance Bloom syndrome complex (BS complex) is necessary for maintenance of genome stability and suppression cancer-causing mutations. Composed a helicase, topoisomerase, two scaffolds, the BS implicated in several steps that ensure high fidelity DNA repair by recombination. One step, called “double Holliday junction dissolution,” ensures untangling at conclusion repair. Here, we used cross-link mass spectrometry to show how assembles. Using biochemical reactions cell complementation...
Protein-protein interactions can be modulated by the methylation of arginine residues. As a means testing this, we recently described conditional two-hybrid system, based on bacterial adenylate cyclase (BACTH) system. Here, have used this system to explore effect in modulating protein-protein subset Saccharomyces cerevisiae methylproteome network. Interactions between yeast hub protein Npl3 and proteins Air2, Ded1, Gbp2, Snp1, Yra1 were first validated absence methylation. The major...
Classical zinc fingers (ZFs) are traditionally considered to act as sequence-specific DNA-binding domains. More recently, classical ZFs have been recognised potential RNA-binding modules, raising the intriguing possibility that classical-ZF transcription factors involved in post-transcriptional gene regulation via direct RNA binding. To date, however, only one ZF-RNA complex, involving TFIIIA, has structurally characterised. Yin Yang-1 (YY1) is a multi-functional factor many regulatory...
The nucleosome remodeling and deacetylase (NuRD) complex remodels the genome in context of both gene transcription DNA damage repair. It is essential for normal development distributed across multiple tissues organisms ranging from mammals to nematode worms. In common with other chromatin-remodeling complexes, however, its molecular mechanism action not well understood only limited structural information available show how assembled. As a step towards understanding structure NuRD complex, we...
Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles steatosis, insulin resistance, cancers and inflammatory fibrotic diseases. In addition, binds to spike protein MERS virus, causing be human cell surface receptor for virus. been identified as potential...
The nucleosome remodeling and deacetylase (NuRD) complex is a chromatin-modifying assembly that regulates gene expression DNA damage repair. Despite its importance, limited structural information describing the complete NuRD available detailed understanding of mechanism therefore lacking. Drawing on from SEC-MALLS, DIA-MS, XLMS, negative-stain EM, X-ray crystallography, NMR spectroscopy, secondary structure predictions, homology models, we applied Bayesian integrative determination to...