A5089637635- Ubiquitin and proteasome pathways
- Peptidase Inhibition and Analysis
- Cancer-related Molecular Pathways
- Tuberculosis Research and Epidemiology
- Respiratory and Cough-Related Research
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- RNA modifications and cancer
- Asthma and respiratory diseases
- HIV/AIDS drug development and treatment
- Chronic Lymphocytic Leukemia Research
- Sarcoidosis and Beryllium Toxicity Research
- Protein Structure and Dynamics
- Biochemical and Molecular Research
- Autophagy in Disease and Therapy
- Neonatal Respiratory Health Research
- Enzyme Structure and Function
- Biopolymer Synthesis and Applications
- Cancer-related gene regulation
- Galectins and Cancer Biology
- Endoplasmic Reticulum Stress and Disease
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Neuropeptides and Animal Physiology
- IL-33, ST2, and ILC Pathways
University of Dundee
2022-2024
Cancer Research UK Manchester Institute
2024
MRC Protein Phosphorylation and Ubiquitylation Unit
2022-2024
Institute of Structural and Molecular Biology
2024
University of Leeds
2024
Medical Research Council
2022
Cancer Research UK Scotland Institute
2020-2021
University of Glasgow
2021
Cancer Research UK
2020-2021
Umeå University
2016
Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with ubiquitin-like protein UFM1 on 60S ribosomal subunit RPL26 (also known as uL24)
Protein UFMylation, i.e., post-translational modification with ubiquitin-fold modifier 1 (UFM1), is essential for cellular and endoplasmic reticulum homeostasis. Despite its biological importance, we have a poor understanding of how UFM1 conjugated onto substrates. Here, use rebuilding approach to define the minimal requirements protein UFMylation. We find that reported cognate E3 ligase UFL1 inactive on own instead requires adaptor UFBP1 form an active complex. Structure predictions suggest...
An essential first step in the post-translational modification of proteins with UFM1, UFMylation, is proteolytic cleavage pro-UFM1 to expose a C-terminal glycine. Of two UFM1-specific proteases (UFSPs) identified humans, only UFSP2 reported be active, since annotated sequence UFSP1 lacks critical catalytic residues. Nonetheless, efficient UFM1 maturation occurs cells lacking UFSP2, suggesting presence another active protease. We herein identify translated from non-canonical start site this...
Abstract Phosphorylation of MDM2 by ATM upon DNA damage is an important mechanism for deregulating MDM2, thereby leading to p53 activation. phosphorylates multiple residues near the RING domain but underlying molecular basis deregulation remains elusive. Here we show that Ser429 phosphorylation selectively enhances ubiquitin ligase activity homodimer not MDM2-MDMX heterodimer. A crystal structure phospho-Ser429 (pS429)-MDM2 bound E2–ubiquitin reveals a unique 3 10 -helical feature present in...
Enzymes have evolved with highly specific values of their catalytic parameters kcat and KM. This poses fundamental biological questions about the selection pressures responsible for evolutionary tuning these parameters. Here we are address enzyme adenylate kinase (Adk) in eukaryotic yeast cells. A plasmid shuffling system was developed to allow quantification relative fitness (calculated from growth rates) response perturbations Adk activity introduced through mutations. Biophysical...
Calcitonin gene-related peptide (CGRP) is contained within and secreted by nerves neuroepithelial bodies in the airway epithelium. To determine whether CGRP a chemoattractant, tracheal epithelial cells isolated from 23 guinea pigs, bronchial seven human donors were grown primary culture for 4 to 5 days. Cell migration was assessed blindwell chemotaxis chamber. A gelatin-coated polycarbonate filter (8-microns pore size) separated upper wells containing x 10(4) lower chemoattractant (either or...
The postjunctional muscarinic receptors mediating contraction of human bronchial smooth muscle have been characterized using four nonselective receptor agonists and eight subtype selective antagonists. Carbachol, methacholine, oxotremorine M (+)-cis-dioxolane all caused concentration-related contractions with a rank order potency (pD2) (7.3 +/- 0.2) > (6.7 carbachol (6.4 0.1) methacholine (5.8 0.2, n = 5 for all). Maximum were not significantly different between agonists, whether expressed...
The p53 tumor suppressor protein is a potent activator of proliferative arrest and cell death. In normal cells, this pathway restrained by degradation mediated the E3-ubiquitin ligase activity MDM2. Oncogenic stress releases from MDM2 control, so activating response. However, many tumors that retain wild-type inappropriately maintain MDM2-p53 regulatory loop in order to continuously suppress activity. We have shown previously single point mutations human RING finger domain prevent...
Abstract Protein UFMylation is emerging as a posttranslational modification essential for endoplasmic reticulum and cellular homeostasis. Despite its biological importance, we have poor understanding of how UFM1 conjugated onto substrates. Here, use rebuilding approach to define the minimal requirements protein UFMylation. We find that reported E3 ligase UFL1 inactive on own identify UFBP1 bind form an active complex. While UFC1 intrinsically Cys-reactive E2, do not any catalytic cysteines...
Hintergrund: Diese Studie untersuchte die Pharmakokinetik, Sicherheit, Verträglichkeit und Pharmakodynamik von 12µg Formoterol, verabreicht alleine über den Genuair Inhalator® oder Aerolizer® in einer Fix-Kombination mit Aclidinium-Bromid Inhalator®.
As a key regulator of the tumour suppressor protein p53, MDM2 is involved in various types cancer and has thus been an attractive drug target. So far, small molecule design primarily focussed on N-terminal p53-binding domain although on-target toxicity effects have reported. Targeting catalytic RING resembles alternative approach to with idea prevent MDM2-mediated ubiquitination p53 while retaining MDM2's ability bind p53. The inhibitors limited by extensive aggregation tendency domain,...
Abstract An essential first step in the posttranslational modification of proteins with UFM1, UFMylation, is proteolytic cleavage pro-UFM1 to expose a C-terminal glycine. Of two UFM1-specific proteases (UFSPs) identified humans, only UFSP2 reported be active since annotated sequence UFSP1 lacks critical catalytic residues. Nonetheless, efficient UFM1 maturation occurs cells lacking suggesting presence another protease. We hereby identify long isoform this Cells both UFSPs show complete loss...
Einleitung: In Kernen von seneszenten Zellen bilden sich Heterochromatin-Domänen aus, die durch Anfärbung mit DAPI und Fluoreszenzmikroskopie nachweisbar sind („SAHF“, Senescence-Associated Heterochromatin Foci [Narita, Cell 2003]). Im Vergleich zur Detektion seneszenter ß-Galactosidase (Dimri, PNAS 1995), ist der Nachweis SAHF weniger zeitaufwendig SAHF-Bildung zudem mechanistisch direkter an zellulären Seneszenz beteiligt (Narita, BJC 2007).
Die Lungensarkoidose verläuft im Allgemeinen gutartig. Nur ca 10% entwickeln eine Lungenfibrose. Allerdings sind die späten Röntgentypen III und IV durchaus komplikationsträchtig, wie wir anhand dreier Fallberichte (3Männer, Durchschnittsalter 47,7 Jahre) berichten.
Einleitung: Lungenfibroblasten von Patienten mit Emphysem zeigen in vitro eine reduzierte Proliferationsrate. Hinweise auf vorzeitige Alterung ergeben sich u.a. aus einer erhöhten Gen-/Proteinexpression Insulin-like growth factor-binding protein (IGFBP)-3 und -7 (Müller et al. 2006). IGFBPs interagieren Insulin IGF, gesteigerte Insulin/IGF-1 vermittelte Signaltransduktion wird der Induktion zellulären Seneszenz Verbindung gebracht. Diese Untersuchung sollte klären, ob anders diese Faktoren...