A5058534234- Endoplasmic Reticulum Stress and Disease
- Autophagy in Disease and Therapy
- Legionella and Acanthamoeba research
- Heat shock proteins research
- Genetic Neurodegenerative Diseases
- Cancer, Hypoxia, and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Chemical Synthesis and Reactions
- RNA regulation and disease
- Polyoxometalates: Synthesis and Applications
- RNA Research and Splicing
- Enzyme Structure and Function
- Carbon dioxide utilization in catalysis
- ATP Synthase and ATPases Research
- Vibrio bacteria research studies
- Botanical Research and Chemistry
- Toxin Mechanisms and Immunotoxins
- Pancreatic function and diabetes
- Organometallic Complex Synthesis and Catalysis
- Inorganic Fluorides and Related Compounds
- Religion and Society Interactions
- Chemical Synthesis and Analysis
- Heme Oxygenase-1 and Carbon Monoxide
- Genetics and Neurodevelopmental Disorders
- Historical and Linguistic Studies
University of Cambridge
2016-2023
Midland College
2022
Transnational Press London
2022
The Francis Crick Institute
2022
Institute for Medical Research
2016
University of Bristol
2013
The small molecule ISRIB antagonizes the activation of integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange for eIF2. We have found that ISRIB-mediated acceleration eIF2B's activity vitro is observed preferentially presence attenuated mutations desensitize eIF2B to inhibitory effect ISRIB's efficacy as an ISR inhibitor cells also depends on Cryoelectron...
The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and an intracellular calcium storage compartment, facilitating calcium-release-dependent cellular processes. ER depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in impact organellar proteostasis. Here, we report that selectively affects dynamics abundant Hsp70 chaperone BiP, by enhancing its affinity ADP. In calcium-replete ER, ADP...
Abstract Dysfunction of the endoplasmic reticulum (ER) in insulin‐producing beta cells results cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy‐onset mellitus severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation FICD . The gene encodes bifunctional Fic domain‐containing enzyme that regulates ER Hsp70 chaperone, BiP, via catalysis two antagonistic reactions: inhibitory AMPylation stimulatory...
Article18 September 2019Open Access Source DataTransparent process An oligomeric state-dependent switch in the ER enzyme FICD regulates AMPylation and deAMPylation of BiP Luke A Perera orcid.org/0000-0002-0032-1176 Cambridge Institute for Medical Research, University Cambridge, UK Search more papers by this author Claudia Rato orcid.org/0000-0002-3971-046X Yahui Yan orcid.org/0000-0001-6934-9874 Lisa Neidhardt orcid.org/0000-0003-0256-5040 Stephen H McLaughlin orcid.org/0000-0001-9135-6253...
Abstract The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both AMPylation and deAMPylation are catalysed single ER-localised enzyme, FICD. Here we present crystallographic solution structures of Michaelis complex formed between mammalian AMPylated latter, via its tetratricopeptide repeat domain, binds surface that specific to ATP-state chaperones, explaining the exquisite selectivity FICD for BiP’s...
Significance statement Some 25 years ago it was discovered that the activity of ER chaperone BiP is regulated by covalent modification, nature which, AMPylation (not ADPribosylation, as had long been thought) and enzyme responsible, FICD, have only recently identified. Genetic inactivation FICD in vitro studies purified substrate done much to clarify biochemical consequences modification its underlying logic: As stress wanes, uses ATP AMPylate Thr518 locking a relatively inactive...
Abstract AMPylation is an inactivating modification that matches the activity of major endoplasmic reticulum (ER) chaperone BiP to burden unfolded proteins. A single ER-localised Fic protein, FICD (HYPE), catalyses both and deAMPylation BiP. However, basis for switch in FICD’s unknown. We report on transition from a dimeric enzyme, deAMPylates BiP, monomer with potent activity. Mutations dimer interface or residues tracing inhibitory relay enzyme’s active site favour vitro cells....
Abstract The small molecule ISRIB antagonises the activation of integrated stress response (ISR) by phosphorylated translation initiation factor 2, eIF2(αP). and eIF2(αP) bind distinct sites in their common target, eIF2B, a guanine nucleotide exchange (GEF) for eIF2. We have found that ISRIB-mediated acceleration eIF2B activity vitro is observed preferentially presence attenuated mutations desensitise to inhibitory effects ISRIB’s efficacy as an ISR inhibitor cells also depends on Cryo-EM...
Abstract The metazoan endoplasmic reticulum (ER) serves both as a hub for maturation of secreted proteins and an intracellular calcium storage compartment, facilitating release-dependent cellular processes. ER depletion robustly activates the unfolded protein response (UPR). However, it is unclear how fluctuations in impact organellar proteostasis. Here we report that selectively affects dynamics abundant Hsp70 chaperone BiP, by enhancing its affinity ADP. In replete ER, ADP rebinding to...
Bodhicitta and Charity:A Comparison Luke Perera The object of this paper is to present a comparison bodhicitta charity. These concepts are central their respective traditions (Mahāyāna Buddhism, Christianity), for the sake keeping within reasonable limits I will focus on two sets texts: writings Indian Buddhist monk Śāntideva (late seventh eighth centuries ce) those French Catholic nun Thérèse Lisieux (1873–1897). My intention that help clarify similarities differences between provide...
ABSTRACT Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results cell loss and diabetes mellitus. Here we report on 5 individuals from three different consanguineous families with infancy-onset mellitus severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation FICD . The gene encodes bifunctional Fic domain-containing enzyme that regulates ER Hsp70 chaperone, BiP, via catalysis two antagonistic reactions: inhibitory AMPylation stimulatory...
Abstract The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both AMPylation and deAMPylation are catalysed single ER-localised enzyme, FICD. Here we present long-sought crystallographic solution structures of Michaelis complex formed between mammalian AMPylated latter, via its tetratricopeptide repeat domain, binds surface that specific to ATP-state chaperones, explaining the exquisite selectivity FICD for...