A5063904644- Genetic Neurodegenerative Diseases
- Mitochondrial Function and Pathology
- RNA Research and Splicing
- Amyotrophic Lateral Sclerosis Research
- Ubiquitin and proteasome pathways
- Metabolism and Genetic Disorders
- Protein Structure and Dynamics
- Enzyme Structure and Function
- DNA Repair Mechanisms
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Glycosylation and Glycoproteins Research
- Metabolomics and Mass Spectrometry Studies
- Nitric Oxide and Endothelin Effects
- Peptidase Inhibition and Analysis
- Amino Acid Enzymes and Metabolism
- RNA modifications and cancer
- Cancer-related Molecular Pathways
- RNA and protein synthesis mechanisms
- Neurogenetic and Muscular Disorders Research
- Genetic factors in colorectal cancer
- Connexins and lens biology
- Invertebrate Immune Response Mechanisms
- Prion Diseases and Protein Misfolding
- Phagocytosis and Immune Regulation
- Heme Oxygenase-1 and Carbon Monoxide
The Francis Crick Institute
2004-2024
Cancer Research UK
2005
The Honourable Society of Lincoln's Inn
2005
Birkbeck, University of London
2005
University of Parma
2000
Variants of UNC13A, a critical gene for synapse function, increase the risk amyotrophic lateral sclerosis and frontotemporal dementia
SARS-CoV-2 spike N-terminal domain harbors a potent epitope that can be modulated by binding of natural linear tetrapyrroles.
Abstract RAD52 is important for the repair of DNA double-stranded breaks 1,2 , mitotic synthesis 3–5 and alternative telomere length maintenance 6,7 . Central to these functions, promotes annealing complementary single-stranded (ssDNA) 8,9 provides an BRCA2/RAD51-dependent homologous recombination 10 Inactivation in homologous-recombination-deficient BRCA1 - or BRCA2 -defective cells synthetically lethal 11,12 aberrant expression associated with poor cancer prognosis 13,14 As a consequence,...
The Josephin domain plays an important role in the cellular functions of ataxin-3, protein responsible for neurodegenerative Machado–Joseph disease. We have determined solution structure and shown that it belongs to family papain-like cysteine proteases, sharing highest degree structural similarity with bacterial staphopain. A currently unique feature is a flexible helical hairpin formed by 32-residue insertion, which could determine substrate specificity. By using availability NMR chemical...
Aggregation of expanded polyglutamine (polyQ) seems to be the cause various genetic neurodegenerative diseases. Relatively little is known as yet about polyQ structure and mechanism that induces aggregation. We have characterised solution in a proteic context using model system based on glutathione S ‐transferase fusion proteins. A wide range biophysical techniques was applied. For first time, nuclear magnetic resonance used observe directly selectively conformation pathological range....
Abstract Chemical and thermal denaturation of calmodulin has been monitored spectroscopically to determine the stability for intact protein its two isolated domains as a function binding Ca 2+ or Mg . The reversible urea unfolding either apo‐domain follows two‐state mechanism with relatively low δG° 20 values ˜2.7 (N‐domain) ˜1.9 kcal/mol (C‐domain). apo‐C‐domain is significantly unfolded at normal temperatures (20‐25 °C!. greater affinity C‐domain causes it be more stable than N‐domain [Ca...
Anomalous expansion of a polyglutamine (polyQ) tract in the protein ataxin-3 causes spinocerebellar ataxia type 3, an autosomal dominant neurodegenerative disease. Very little is known about structure and function ataxin-3, although this information would undoubtedly help to understand why expanded forms insoluble nuclear aggregates neuronal cell death. With aim establishing domain architecture role polyQ within context, we have studied human murine orthologues using combination techniques,...
Abstract Joseph‐Machado is an incurable neurodegenerative disease caused by toxic aggregation of ataxin‐3, a ubiquitin‐specific cysteine protease, involved in the ubiquitin‐proteasome pathway and known to bind poly‐ubiquitin chains four or more subunits. The enzymatic site resides N‐terminal josephin domain ataxin‐3. We have characterized ubiquitin‐binding properties showed that, unexpectedly, contains two contiguous but distinct sites. One close cleft exploits induced fit mechanism, which...
Protein aggregation is under intense scrutiny because of its role in human disease. Although increasing evidence indicates that protein native states are highly protected against aggregation, the specific protection mechanisms poorly understood. Insight into such can be gained through study relatively few proteins aggregate conditions. Ataxin-3, responsible for Spino-cerebellar ataxia type 3, a polyglutamine expansion disease, represents one examples. Polyglu-tamine central determining...
Several enzymes can simultaneously interact with multiple intracellular metabolites, however, how the allosteric effects of distinct ligands are integrated to coordinately control enzymatic activity remains poorly understood. We addressed this question using, as a model system, glycolytic enzyme pyruvate kinase M2 (PKM2). show that PKM2 activator fructose 1,6-bisphosphate (FBP) alone promotes tetramerisation and increases activity, but addition inhibitor L-phenylalanine (Phe) prevents...
The pathogen Salmonella, which causes significant human morbidity and mortality, encodes an effector kinase, SteC, mediates actin polymerisation cell migration. Given the minimal nature of its kinase domain, it remains unclear how SteC is catalytically active this activity regulated. Here, we show that activated following phosphorylation highly conserved S379 residue by a host kinase. Phosphorylation dramatically increases nucleotide binding affinity enabling substrate promoting...
Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders caused by the expansion of CAG codon repeats, which code for polyQ in corresponding gene products. These associated with presence amyloid-like protein aggregates, induced expansion. It has been suggested that soluble aggregates rather than mature fibrillar toxic species, and aggregation properties can be strongly modulated surrounding context. To assess importance carrier aggregation, we have studied misfolding pathway...
Fibrillar aggregation of the protein ataxin-3 is linked to inherited neurodegenerative disorder Spinocerebellar ataxia type 3, a member polyQ expansion disease family. We previously reported that and stability nonpathological form ataxin-3, carrying an unexpanded tract, are modulated by its N-terminal Josephin domain. It was also shown expanded aggregates via two-stage mechanism initially involving self-association, followed polyQ-dependent step. Despite this recent progress, however, exact...
It is now accepted that reactive oxygen species (ROS) are not only dangerous oxidative agents but also chemical mediators of the redox cell signaling and innate immune response. A central role in ROS‐controlled production played by NADPH oxidases (NOXs), a group seven membrane‐bound enzymes (NOX1‐5 DUOX1‐2) whose unique function to produce ROS. Here, we describe regulation NOX5, widespread family member present cyanobacteria, protists, plants, fungi, animal kingdom. We show calmodulin‐like...
Iron–sulphur (Fe-S) clusters are ubiquitous co-factors which require multi-protein systems for their synthesis. In Mycobacterium tuberculosis, the Rv1460-Rv1461-Rv1462-Rv1463-csd-Rv1465-Rv1466 operon (suf operon) encodes primary Fe-S cluster biogenesis system. The first gene in this operon, Rv1460, shares homology with cyanobacterial SufR, functions as a transcriptional repressor of sufBCDS operon. Rv1460's function M. tuberculosis has however not been determined. study, we demonstrate that...
MutSα and MutSβ play important roles in DNA mismatch repair are linked to inheritable cancers degenerative disorders. Here, we show that MSH2 MSH3, the two components of MutSβ, bind SLX4 protein, a scaffold for assembly SLX1-SLX4-MUS81-EME1-XPF-ERCC1 (SMX) trinuclease complex. SMX promotes resolution Holliday junctions (HJs), which intermediates homologous recombinational repair. We find binds HJs stimulates their by SLX1-SLX4 or reactions dependent upon direct interactions between SLX4. In...
An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The repeats are transcribed both sense antisense directions to generate distinct dipeptide proteins, which poly(GA), poly(GR), poly(PR) have been implicated contributing neurodegeneration. Poly(PR) binding RNA may contribute toxicity, but analysis poly(PR)-RNA on transcriptome-wide scale has not yet carried out. We therefore performed crosslinking...