A5002238592- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Genomics and Rare Diseases
- Genomics and Phylogenetic Studies
- Bioinformatics and Genomic Networks
- Microtubule and mitosis dynamics
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Genetic Associations and Epidemiology
- Ubiquitin and proteasome pathways
- Microbial Metabolic Engineering and Bioproduction
- Histone Deacetylase Inhibitors Research
- Mass Spectrometry Techniques and Applications
- Protist diversity and phylogeny
- Genetic and Kidney Cyst Diseases
- Protein Degradation and Inhibitors
- Advanced Proteomics Techniques and Applications
- Computational Drug Discovery Methods
- RNA modifications and cancer
- Cell Adhesion Molecules Research
- Cancer Genomics and Diagnostics
- Advanced NMR Techniques and Applications
- Retinal Development and Disorders
- Genetics, Bioinformatics, and Biomedical Research
Institute of Genetics and Cancer
2016-2025
University of Edinburgh
2016-2025
Western General Hospital
2013-2024
University of Nottingham
2024
University of Toronto
2006-2023
Medical Research Council
2014-2023
Hospital for Sick Children
2006-2023
SickKids Foundation
2006-2023
University College London
2023
Great Ormond Street Hospital
2023
The synucleins are a family of intrinsically disordered proteins involved in various human diseases. alpha-Synuclein has been extensively characterized due to its role Parkinson's disease where it forms intracellular aggregates, while gamma-synuclein is overexpressed majority late-stage breast cancers. Despite fairly strong sequence similarity between the amyloid-forming regions alpha- and gamma-synuclein, only weak propensity form amyloid fibrils. We hypothesize that different fibrillation...
Intrinsically disordered proteins (IDPs), which lack folded structure and are under nondenaturing conditions, have been shown to perform important functions in a large number of cellular processes. These interesting structural properties that deviate from the random-coil-like behavior exhibited by chemically denatured proteins. In particular, IDPs often observed exhibit significant compaction. this study, we analyzed hydrodynamic radii investigate sequence determinants Net charge proline...
Do young and old protein molecules have the same probability to be degraded? We addressed this question using metabolic pulse-chase labeling quantitative mass spectrometry obtain degradation profiles for thousands of proteins. find that >10% proteins are degraded non-exponentially. Specifically, less stable in first few hours their life stabilize with age. Degradation conserved similar two cell types. Many non-exponentially (NED) subunits complexes produced super-stoichiometric amounts...
The principles of protein assembly A knowledge structure greatly enhances our understanding function. In many cases, function depends on oligomerization. Ahnert et al. used mass spectrometry data together with a large-scale analysis structures complexes to examine the fundamental steps assembly. Systematically combining revealed large set quaternary topologies that were organized into periodic table. Based this table, authors accurately predicted expected frequencies topologies. Science ,...
SummaryIs the order in which proteins assemble into complexes important for biological function? Here, we seek to address this by searching evidence of evolutionary selection ordered protein complex assembly. First, experimentally characterize assembly pathways several heteromeric and show that they can be simply predicted from their three-dimensional structures. Then, mapping gene fusion events identified fully sequenced genomes onto pathways, demonstrate conservation order. Furthermore,...
Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function STING, key adaptor of IFN signaling. Recently, increased levels IFN-stimulated genes (ISGs) were described COPA syndrome. However, the link between and signaling is unknown. We observed elevated ISGs IFN-α blood symptomatic patients. In vitro, both overexpression mutant silencing induced STING-dependent detected an interaction...
Abstract Most known pathogenic mutations occur in protein-coding regions of DNA and change the way proteins are made. Taking protein structure into account has therefore provided great insight molecular mechanisms underlying human genetic disease. While there been much focus on how can disrupt thus cause a loss function (LOF), alternative mechanisms, specifically dominant-negative (DN) gain-of-function (GOF) effects, less understood. Here, we investigate protein-level effects missense...
Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease ischemic stroke. CHIP is driven by somatic mutations hematopoietic stem progenitor cells (HSPCs). Because HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from leukemia. defined as the proliferative advantage over carrying no or only neutral mutations. If...
Abstract The assessment of variant effect predictor (VEP) performance is fraught with biases introduced by benchmarking against clinical observations. In this study, building on our previous work, we use independently generated measurements protein function from deep mutational scanning (DMS) experiments for 26 human proteins to benchmark 55 different VEPs, while introducing minimal data circularity. Many top‐performing VEPs are unsupervised methods including EVE, DeepSequence and ESM‐1v, a...
Abnormal increases in cell size are associated with senescence and cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the remain unknown. We address this question using CDK4/6 inhibitors, arrest G0/G1 licensed treat advanced HR+/HER2- breast cancer. demonstrate that CDK4/6-inhibited overgrow during G0/G1, causing p38/p53/p21-dependent withdrawal. Cell withdrawal is triggered biphasic p21 induction. first wave caused osmotic stress, leading p38- size-dependent...
UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in causing systemic lupus erythematosus (SLE) or chilblain (CBL) as either autosomal dominant recessive traits. As for D34A mutation murine lupus, we recorded gain TLR7 and, to lesser extent, TLR8 activity with I317M (in vitro) G325C vitro ex vivo) variants context SLE. Contrastingly,...
Abstract TLR7 recognizes pathogen-derived single-stranded RNA (ssRNA), a function integral to the innate immune response viral infection. Notably, can also recognize self-derived ssRNA, with gain-of-function mutations in human recently identified cause both early-onset systemic lupus erythematosus (SLE) and neuromyelitis optica. Here, we describe two novel TLR7, F507S L528I. While L528I substitution arose de novo, mutation was present three individuals from same family, including severely...
Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct form cell type– and context-specific microtubule structures is poorly understood. Based on a cohort 12 patients with primary ciliary dyskinesia as well mouse mutants, we identified characterized variants TUBB4B isotype that specifically perturbed centriole cilium biogenesis. Distinct differentially affected dynamics cilia formation...
Abstract Computational methods for assessing the likely impacts of mutations, known as variant effect predictors (VEPs), are widely used in assessment and interpretation human genetic variation, well other applications like protein engineering. Many different VEPs have been released, there is tremendous variability their underlying algorithms, outputs, ways which methodologies predictions shared. This leads to considerable difficulties users trying navigate selection application VEPs. Here,...
Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation type I interferon (IFN) signalling, we identified a cohort individuals heterozygous mutations in PTPN1, encoding protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe clinical phenotype and molecular cellular pathology this new disease. In case series, collected neuroradiological data through collaboration paediatric neurology genetics colleagues across Europe (Czechia, France,...
Protein interactions are often accompanied by significant changes in conformation. We have analyzed the relationships between protein structures and conformational they undergo upon binding. Based this, we introduce a simple measure, relative solvent accessible surface area, which can be used to predict magnitude of binding-induced from either monomeric proteins or bound subunits. Applying this large set complexes suggests that binding common. In addition, observe considerable enrichment...
Protein complexes are assemblies of subunits that have co-evolved to execute one or many coordinated functions in the cellular environment. Functional annotation mammalian protein is critical understanding biological processes, as well disease mechanisms. Here, we used genetic co-essentiality derived from genome-scale RNAi- and CRISPR-Cas9-based fitness screens performed across hundreds human cancer cell lines assign measures functional similarity. From these measures, systematically built...
Abstract Summary: ENSEMBLE is a computational approach for determining set of conformations that represents the structural ensemble disordered protein based on input experimental data. The can be an unfolded or intrinsically state. Here, we introduce latest version program, which has been enhanced to facilitate its general release and includes intuitive user interface, as well new approaches treat data analyse results. Availability implementation: program implemented in C embedded Perl...