A5071674689- RNA Research and Splicing
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Glycosylation and Glycoproteins Research
- Genomics and Phylogenetic Studies
- Genomics and Chromatin Dynamics
- PARP inhibition in cancer therapy
- Carbohydrate Chemistry and Synthesis
- DNA Repair Mechanisms
- Biofuel production and bioconversion
- Neurogenetic and Muscular Disorders Research
- Galectins and Cancer Biology
- Microbial Natural Products and Biosynthesis
- DNA and Nucleic Acid Chemistry
- Antimicrobial Resistance in Staphylococcus
- Peptidase Inhibition and Analysis
- Biomedical Ethics and Regulation
- Bacterial Genetics and Biotechnology
- Amyotrophic Lateral Sclerosis Research
Hospital for Sick Children
2020-2024
University of Toronto
2021-2024
Great Ormond Street Hospital
2022
University College London
2022
SickKids Foundation
2022
University of British Columbia
2016-2020
Significance Many important biological processes occur within biomolecular condensates. Unlike many organelles, these condensates lack a surrounding membrane but are formed by phase separation due to interactions of their molecular components. Although the role intrinsically disordered protein regions (IDRs) in is appreciated and contributing amino acids have been identified, experimentally derived site-specific information reporting on between IDRs condensed phases lacking. Using suite NMR...
Epigenetic modifications of chromatin play a critical role in regulating the fidelity genetic code and controlling translation information into protein components cell. One key posttranslational modification is acetylation histone lysine residues. Molecular dynamics simulations, to smaller extent experiment, have established that increases tails. However, systematic, atomic resolution experimental investigation how this epigenetic mark, focusing on one at time, influences structural...
In recent years, there has been a growing interest in teichoic acids as targets for antibiotic drug design against major clinical pathogens such Staphylococcus aureus, reflecting the disquieting increase resistance and historical success of bacterial cell wall components targets. It is now becoming clear that β-O-GlcNAcylation S. aureus plays role both pathogenicity resistance. Here we present first structure TarS, enzyme responsible polyribitol phosphate β-O-GlcNAcylation. Using divide...
In Escherichia coli, the peptidoglycan cell wall is synthesized by bifunctional penicillin-binding proteins such as PBP1b that have both transpeptidase and transglycosylase activities. The domain a major target of β-lactams, therefore it important to attain detailed understanding its inhibition. glycosyltransferase also considered an excellent antibiotic yet not exploited any clinically approved antibacterials. Herein, we adapt pyrophosphate sensor assay monitor PBP1b-catalyzed...
Many membraneless organelles are thought to be biomolecular condensates formed by phase separation of proteins and other biopolymers. Post-translational modifications (PTMs) can impact protein behavior, although for many PTMs this aspect their function is unknown. O-linked β-D-N-acetylglucosaminylation (O-GlcNAcylation) an abundant form intracellular glycosylation whose roles in regulating condensate assembly dynamics have not been delineated. Using vitro approach, we found that...
The compaction of chromatin into mitotic chromosomes is essential for faithful transmission the genome during cell division. In eukaryotes, chromosome morphogenesis regulated by condensin complex, though exact mechanism used to target and initiate condensation not understood. Here, we reveal that contains an intrinsically disordered region (IDR) modulates its association with in early mitosis exhibits phase separation. We describe DNA-binding motifs within IDR that, upon deletion, inflict...
Poly(ADP-ribose) polymerase 1 (PARP1) is one of the first responders to DNA damage and plays crucial roles in recruiting repair proteins through its activity - poly(ADP-ribosyl)ation (PARylation). The enrichment at sites has been described as formation a biomolecular condensate. However, it not understood how PARP1 PARylation contribute organization condensates. Using recombinant human
O-GlcNAc transferase (OGT) is an essential glycosylating enzyme that catalyzes the addition of N-acetylglucosamine to serine or threonine residues nuclear and cytoplasmic proteins. The glycosylates a broad range peptide sequences prediction glycosylation sites has proven challenging. lack experimentally verified set polypeptide are not glycosylated by OGT made legitimate more difficult. Here, we tested number intrinsically disordered protein regions as substrates establish OGT. negative data...
is a major human pathogen that has acquired alarming broad-spectrum antibiotic resistance. One group of secreted toxins with key roles during infection the phenol-soluble modulins (PSMs). PSMs are amphipathic, membrane-destructive cytolytic peptides exported to host-cell environment by designated adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, PSM transporter (PmtABCD). Here, we demonstrate minimal Pmt unit necessary for export PmtCD and provide its first atomic...
Summary Mutations in the RNA binding protein (RBP) FUS cause amyotrophic lateral sclerosis (ALS) and result its nuclear depletion cytoplasmic mislocalisation, with gain of function thought to be crucial pathogenesis. Here, we show that expression mutant at physiological levels drives translation inhibition both mouse human motor neurons. Rather than acting directly on machinery, find forms condensates promote phase separation FMRP, another RBP associated neurodegeneration robustly involved...
ABSTRACT Many membraneless organelles are thought to be biomolecular condensates formed by phase separation of proteins and other biopolymers. Post-translational modifications (PTMs) can impact protein behavior, although for many PTMs this aspect their function is unknown. O -linked β-D- N -acetylglucosaminylation ( -GlcNAcylation) an abundant form intracellular glycosylation whose roles in regulating condensate assembly dynamics have not been delineated. Using vitro approach, we found that...
Abstract O-GlcNAc transferase (OGT) is an essential glycosylating enzyme that catalyzes the addition of N-acetylglucosamine to serine or threonine residues nuclear and cytoplasmic proteins. The glycosylates a broad range peptide sequences prediction glycosylation sites has proven challenging. lack experimentally verified set polypeptide are not glycosylated by OGT made legitimate more difficult. Here, we tested number intrinsically disordered protein regions as substrates establish OGT....