A5088807574- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- RNA regulation and disease
- RNA modifications and cancer
- Endoplasmic Reticulum Stress and Disease
- Crystallization and Solubility Studies
- Magnetism in coordination complexes
- X-ray Diffraction in Crystallography
- Polyoxometalates: Synthesis and Applications
- Developmental Biology and Gene Regulation
- Cancer-related gene regulation
- Biochemical and Molecular Research
- Protein Structure and Dynamics
- Fluorine in Organic Chemistry
- Congenital heart defects research
- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Hippo pathway signaling and YAP/TAZ
- Catalysis and Hydrodesulfurization Studies
- Wnt/β-catenin signaling in development and cancer
- CRISPR and Genetic Engineering
- PI3K/AKT/mTOR signaling in cancer
- Inorganic Fluorides and Related Compounds
- Synthesis and characterization of novel inorganic/organometallic compounds
- Catalytic Processes in Materials Science
University of Manchester
2013-2023
Manchester Academic Health Science Centre
2017-2022
Cellular Research (United States)
2018
Babraham Institute
2016
King's College London
2016
University of Exeter
2016
Indiana University Bloomington
2011
Abstract Protein synthesis in eukaryotes is controlled by signals and stresses via a common pathway, called the integrated stress response (ISR). Phosphorylation of translation initiation factor eIF2 alpha at conserved serine residue mediates translational control ISR core. To provide insight into mechanism we have determined structures both phosphorylated unphosphorylated forms bound with its nucleotide exchange eIF2B electron cryomicroscopy. The reveal that undergoes large rearrangements...
A new set of wheels: Substituting a chromium ion in [Cr8F8(O2CCMe3)16] with one number alternative transition metals has yielded an unprecedented family heterometallic wheel complexes (see picture), supported at their centers by secondary ammonium ions. Both 3d (Mn, Fe, Co, Ni) and 4d (Cd) have been employed to produce such structures, the magnetic spectroscopic properties which are discussed.
Protein synthesis factor eIF2 delivers initiator tRNA to the ribosome. Two proteins regulate its G-protein cycle: eIF5 has both GTPase-accelerating protein (GAP) and GDP dissociation inhibitor (GDI) functions, eIF2B is guanine nucleotide exchange (GEF). In this study, we used protein–protein interaction assays monitor kinetics of release from eIF2•GDP/eIF5 GDI complex determine effect on release. We demonstrate that a second activity as displacement (GDF) can recruit prior GEF action. found...
Abstract eIF2B facilitates and controls protein synthesis in eukaryotes by mediating guanine nucleotide exchange on its partner eIF2. We combined mass spectrometry (MS) with chemical cross-linking, surface accessibility measurements homology modelling to define subunit stoichiometry interactions within Although it is generally accepted that a pentamer of five non-identical subunits (α–ε), here we show decamer. MS cross-linking complexes allows us propose model for the arrangements where...
The structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only to contain amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized variable combinations developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels PPT-reporters studies...
Phosphorylation of eIF2α controls translation initiation by restricting the levels active eIF2-GTP/Met-tRNAi ternary complexes (TC). This modulates expression all eukaryotic mRNAs and contributes to cellular integrated stress response. Key controlling activity eIF2 are factors eIF2B eIF5, thought primarily function with eIF2-GDP TC respectively. Using a steady-state kinetics approach purified proteins we demonstrate that binds equal affinity irrespective presence or absence competing guanine...
Structured Fe-ZSM-5 zeolite supported on silicon carbide (SiC) foam catalyst was develop and applied as the packed bed catalytic reactor (FBCR) to liquid phase wet peroxide oxidation (CWPO) of phenol under flow conditions. Fe catalysts were uniformly incorporated into ZSM-5 coatings using chemical vapour deposition (CVD). Fluid analysis FBCR performed by varying rate, showing transition type from plug continuous stirred tank at about 1 ml min−1. Systematic investigation CWPO within...
The translation factor eIF5 is an important partner of eIF2, directly modulating its function in several critical steps. First, binds eIF2/GTP/Met-tRNAiMet ternary complex (TC), promoting recruitment to 40S ribosomal subunits. Secondly, GTPase activating promotes eIF2 dissociation for subunit joining. Finally, GDP inhibition (GDI) activity can antagonize reactivation by competing with the guanine exchange (GEF), eIF2B. C-terminal domain (CTD) eIF5, a W2-type HEAT domain, mediates interaction...
In response to oxidative stress cells reprogram gene expression enhance levels of antioxidant enzymes and promote survival. Saccharomyces cerevisiae the polysome-interacting La-related proteins (LARPs) Slf1 Sro9 aid adaptation protein synthesis during by undetermined means. To gain insight in their mechanisms action responses, we determined LARP mRNA binding positions stressed unstressed cells. Both bind within coding regions stress-regulated enzyme other highly translated mRNAs both optimal...
Ein Satz neuer Reifen: Die Substitution eines Chrom-Ions im Komplex [Cr8F8(O2CCMe3)16] durch andere Übergangsmetalle führte zu Heterometall-"Rad"-Komplexen (siehe Bild), die in ihren Zentren sekundäre Ammoniumionen gestützt werden. Sowohl 3d- (Mn, Fe, Co, Ni) als auch 4d-Metalle (Cd) wurden zur Herstellung derartiger Strukturen eingesetzt, deren magnetische und spektroskopische Eigenschaften diskutiert
Zona occludens (ZO) proteins are molecular scaffolds localized to cell junctions, which regulate epithelial integrity in mammals. Using newly generated null alleles, we demonstrate that polychaetoid (pyd), the unique Drosophila melanogaster ZO homologue, regulates accumulation of adherens junction-localized receptors, such as Notch, although it is dispensable for polarization. Pyd positively Notch signaling during sensory organ development but acts negatively on restrict ovary germline stem...
Non-membrane-bound compartments such as P-bodies (PBs) and stress granules (SGs) play important roles in the regulation of gene expression following environmental stresses. We have systematically quantitatively determined protein mRNA composition PBs SGs formed before after nutrient stress. find that high molecular weight (HMW) complexes exist prior to glucose depletion we propose may act seeds for further condensation proteins forming mature SGs. identify an enrichment with low complexity...
WW domains target proline-tyrosine (PY) motifs and frequently function as tandem pairs. When studied in isolation, single are notably promiscuous regulatory mechanisms undoubtedly required to ensure selective interactions. Here, we show that the fourth domain (WW4) of Suppressor Deltex, a modular Nedd4-like protein down-regulates Notch receptor, is primary mediator direct interaction with Notch-PY motif. A natural Trp Phe substitution WW4 reduces its affinity for general PY sequences...
We recently showed in a publication Nature that the eukaryotic translation initiation factor eIF5 has second regulatory function and is GDI (GDP dissociation inhibitor) addition to its previously characterized role as GAP (GTPase accelerating protein). These findings provide new insight into mechanism of cells. Additional show critical for normal regulation protein synthesis by phosphorylation eIF2α at ser51. Because eIF2 ubiquitous mode translational control these results are broad...
In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. GDP/GTP status is regulated by eIF5 (GAP GDI functions) eIF2B (GEF GDF activities), while eIF2α phosphorylation in response diverse signals a major point of translational control. Here we characterize growth suppressor mutation eIF2β that prevents alters cellular responses reduced activity, including control GCN4 translation. By monitoring the binding fluorescent nucleotides...
A novel fluoride-centered triangular-bridged carboxylate complex, [Ni2Cr(μ3-F)(O2C(t)Bu)6(HO2C(t)Bu)3] (1), is reported. Simple postsynthetic substitution of the terminal pivalic acids in 1 with pyridine and 4-methylpyridine led to isolation [Ni2Cr(μ3-F)(O2C(t)Bu)6(C5H5N)3] (2) [Ni2Cr(μ3-F)(O2C(t)Bu)6((4-CH3)C5H4N)3] (3). Structural magnetic characterizations carried out on series reveal a dominating antiferromagnetic interaction between nickel chromium centers leading an S = (1)/2 ground...
The regulation of translation provides a rapid and direct mechanism to modulate the cellular proteome. In eukaryotes, an established model for recruitment ribosomes mRNA depends upon set conserved initiation factors. Nevertheless, how cells orchestrate define selection individual mRNAs translation, as opposed other potential cytosolic fates, is poorly understood. We have previously found significant variation in interaction between array Indeed, can be separated into different classes based...
eIF2B is the guanine nucleotide exchange factor (GEF) required for cytoplasmic protein synthesis initiation in eukaryotes and its regulation within integrated stress response (ISR). It activates partner eIF2, thereby promoting translation initiation. Here we provide evidence through biochemical genetic approaches that can bind directly to GTP this enhance rate of GEF activity toward eIF2-GDP vitro. binds a subcomplex eIF2Bγ ε subunits. The amino-terminal domain shares structural homology...
ABSTRACT Non-membrane-bound compartments such as P-bodies (PBs) and stress granules (SGs) play important roles in the regulation of gene expression following environmental stresses. We have systematically determined protein mRNA composition PBs SGs formed response to a common condition imposed by glucose depletion. find that high molecular weight (HMW) complexes exist prior depletion may act seeds for further condensation proteins forming mature SGs. Both before after depletion, these HMW...
Abstract By interacting with the mRNA 5′ cap, translation initiation factor eIF4E plays a critical role in selecting mRNAs for protein synthesis eukaryotic cells. Caf20 is member of family proteins found across eukaryotes termed 4E-BPs, which compete eIF4G interaction eIF4E. independently interacts ribosomes. Thus, modulates selection process via poorly understood mechanisms. Here we performed unbiased mutagenesis to characterise regions are important and binding entirely dependent on...