A5002273796- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Carbohydrate Chemistry and Synthesis
- Lysosomal Storage Disorders Research
- Viral Infections and Immunology Research
- RNA Research and Splicing
- Glycosylation and Glycoproteins Research
- Cellular transport and secretion
- Genomics and Phylogenetic Studies
- RNA regulation and disease
- Phytase and its Applications
- Trypanosoma species research and implications
- Fungal and yeast genetics research
- Enzyme Production and Characterization
- Cytomegalovirus and herpesvirus research
- Infrastructure Maintenance and Monitoring
- Herpesvirus Infections and Treatments
- Cancer Research and Treatments
- Enzyme function and inhibition
- Transport Systems and Technology
- Asphalt Pavement Performance Evaluation
- Enzyme Structure and Function
- Fungal Plant Pathogen Control
- Biomedical Ethics and Regulation
- Balance, Gait, and Falls Prevention
University of York
1983-2025
RTI International
2023
University of Cambridge
2013-2022
MRC Laboratory of Molecular Biology
2016-2020
Addenbrooke's Hospital
2019-2020
University of Utah
2020
University of Mississippi
2019
Wellcome Trust
2015-2017
Institute for Medical Research
2015
University of Nebraska–Lincoln
1952
Abstract To conserve energy during starvation and stress, many organisms use hibernation factor proteins to inhibit protein synthesis protect their ribosomes from damage 1,2 . In bacteria, two families of factors have been described, but the low conservation these huge diversity species, habitats environmental stressors confounded discovery 3–6 Here, by combining cryogenic electron microscopy, genetics biochemistry, we identify Balon, a new in cold-adapted bacterium Psychrobacter urativorans...
Newly transcribed eukaryotic precursor messenger RNAs (pre-mRNAs) are processed at their 3' ends by the ~1-megadalton multiprotein cleavage and polyadenylation factor (CPF). CPF cleaves pre-mRNAs, adds a polyadenylate tail, triggers transcription termination, but it is unclear how its various enzymes coordinated assembled. Here, we show that nuclease, polymerase, phosphatase activities of yeast organized into three modules. Using electron cryomicroscopy, determined 3.5-angstrom-resolution...
Cleavage and polyadenylation factor (CPF/CPSF) is a multi-protein complex essential for formation of eukaryotic mRNA 3ʹ ends. CPF cleaves pre-mRNAs at specific site adds poly(A) tail. The cleavage reaction defines the end mature mRNA, thus activity endonuclease highly regulated. Here, we show that reconstitution pre-mRNA with recombinant yeast proteins requires incorporation Ysh1 into an eight-subunit "CPFcore" complex. also accessory factors IA IB, which bind substrate CPF, likely...
Abstract Hunter syndrome is a rare but devastating childhood disease caused by mutations in the IDS gene encoding iduronate-2-sulfatase, crucial enzyme lysosomal degradation pathway of dermatan sulfate and heparan sulfate. These complex glycosaminoglycans have important roles cell adhesion, growth, proliferation repair, their recycling lysosome essential for cellular maintenance. A variety disease-causing been identified throughout gene. However, understanding molecular basis has impaired...
Abstract Background A decline in the discovery of new antibacterial drugs, coupled with a persistent rise occurrence drug-resistant bacteria, has highlighted antibiotics as diminishing resource. The future development drugs novel activities requires detailed understanding adaptive responses to existing compounds. This study uses Streptomyces coelicolor A3(2) model system determine genome-wide transcriptional response following exposure three (vancomycin, moenomycin and bacitracin) that...
Sphingolipids are essential components of cellular membranes and defects in their synthesis or degradation cause severe human diseases. The efficient sphingolipids the lysosome requires lipid-binding saposin proteins hydrolytic enzymes. glycosphingolipid galactocerebroside is primary lipid component myelin sheath degraded by hydrolase β-galactocerebrosidase (GALC). This enzyme SapA for processing either these causes a neurodegenerative disorder, Krabbe disease. Here we present structure...
Modified azasugar molecules have been synthesized and characterized as excellent pharmacological chaperone candidates to treat the neurodegenerative disorder Krabbe disease.
Significance Defects in the enzyme β-galactocerebrosidase (GALC) result devastating neurodegenerative disorder Krabbe disease. GALC is responsible for degradation and recycling of glycosphingolipids that form primary lipid component myelin sheath insulates nerve cells. A detailed understanding how processes substrate will facilitate development new drug therapies This study reveals a series structural snapshots captured during different steps catalytic cycle. These structures identify...
Herpesviruses acquire their membrane envelopes in the cytoplasm of infected cells via a molecular mechanism that remains unclear. Herpes simplex virus (HSV)−1 proteins pUL7 and pUL51 form complex required for efficient envelopment. We show interaction between homologues is conserved across human herpesviruses, as association with trans-Golgi membranes. characterized HSV-1 pUL7:pUL51 by solution scattering chemical crosslinking, revealing 1:2 can higher-order oligomers solution, we solved...
The product of the interferon-stimulated gene C19orf66, Shiftless (SHFL), restricts human immunodeficiency virus replication through downregulation efficiency viral gag/pol frameshifting signal. In this study, we demonstrate that bacterially expressed, purified SHFL can decrease programmed ribosomal in vitro at a variety sites, including RNA pseudoknot-dependent signals coronaviruses IBV, SARS-CoV and SARS-CoV-2, protein-dependent stimulators cardioviruses EMCV TMEV. also reduced stop-codon...
Abstract Ribosome heterogeneity is a paradigm in biology, pertaining to the existence of structurally distinct populations ribosomes within single organism or cell. This concept suggests that pools have different functional properties and may be used translate specific mRNAs. However, it unknown what extent structural reflects genuine specialization rather than stochastic variations ribosome assembly. Here, we address this question by combining cryo-electron microscopy tomography observe...
Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase ( GALC ). The correct targeting of to lysosome essential for degradation glycosphingolipids including primary lipid component myelin. Over 100 different mutations have been identified that cause but mechanisms which they remain unclear. We generated monoclonal antibodies against full‐length human and used these monitor trafficking processing variants cell‐based assays...
Abstract Programmed –1 ribosomal frameshifting (PRF) in cardioviruses is activated by the 2A protein, a multi-functional virulence factor that also inhibits cap-dependent translational initiation. Here we present X-ray crystal structure of and show it selectively binds to pseudoknot-like conformation PRF stimulatory RNA element viral genome. Using optical tweezers, demonstrate stabilises this element, likely explaining increase efficiency presence 2A. Next, strong interaction between small...
Bacterial resistance to the glycopeptide antibiotic teicoplanin shows some important differences from closely related compound vancomycin. They are currently poorly understood but may reflect significant in mode of action each antibiotic. Streptomyces coelicolor possesses a vanRSJKHAX gene cluster that when expressed confers both vancomycin and teicoplanin. The is mediated by enzymes encoded vanKHAX, not vanJ. vanHAX effect reprogramming peptidoglycan biosynthesis, which considered be...
Many viruses utilize programmed -1 ribosomal frameshifting (-1 PRF) to express additional proteins or produce frameshift and non-frameshift protein products at a fixed stoichiometric ratio. PRF is also utilized in the expression of small number cellular genes. Frameshifting typically stimulated by signals contained within mRNA: 'slippery' sequence 3'-adjacent RNA structure. Recently, we showed that encephalomyocarditis virus (EMCV) trans-activated viral 2A protein, leading temporal change...
Mmi1 is an essential RNA-binding protein in the fission yeast Schizosaccharomyces pombe that eliminates meiotic transcripts during normal vegetative growth. contains a YTH domain binds specific RNA sequences, targeting mRNAs for degradation. The of uses noncanonical surface includes contacts outside conserved fold. Here, we report N-terminal extension proximal to enhances binding. Using X-ray crystallography, NMR, and biophysical methods, show this low-complexity region becomes more ordered...
The 2A protein of Theiler's murine encephalomyelitis virus (TMEV) acts as a switch to stimulate programmed -1 ribosomal frameshifting (PRF) during infection. Here, we present the X-ray crystal structure TMEV and define how it recognises stimulatory RNA element. We demonstrate critical role for bases upstream originally predicted stem-loop, providing evidence pseudoknot-like conformation suggesting that recognition this pseudoknot by beta-shell proteins is conserved feature in cardioviruses....
Microbiological data have been presented on the distribution of vit. B12 in tissues and organs chicks fed a purified diet containing high level B12. Kidney was found to contain most while liver pancreas lesser quantities. Muscle, except for heart, is low under these conditions. A comparison results with other published indicates that certain organs, particularly kidney, pancreas, ability store appreciable quantities