A5063875453- Protein Structure and Dynamics
- RNA and protein synthesis mechanisms
- Enzyme Structure and Function
- Genomics and Phylogenetic Studies
- Cancer, Hypoxia, and Metabolism
- Glycosylation and Glycoproteins Research
- Bioinformatics and Genomic Networks
- Receptor Mechanisms and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Machine Learning in Bioinformatics
- Congenital gastrointestinal and neural anomalies
- Computational Drug Discovery Methods
- DNA and Nucleic Acid Chemistry
- Metabolism, Diabetes, and Cancer
- Pluripotent Stem Cells Research
- Metabolomics and Mass Spectrometry Studies
- Prion Diseases and Protein Misfolding
- Neurogenesis and neuroplasticity mechanisms
- Signaling Pathways in Disease
- Infant Nutrition and Health
- Microbial Metabolic Engineering and Bioproduction
- Malaria Research and Control
- Protein Kinase Regulation and GTPase Signaling
- Developmental Biology and Gene Regulation
- Cardiomyopathy and Myosin Studies
The Francis Crick Institute
2010-2024
Heptares Therapeutics (United Kingdom)
2023
Thomas Young Centre
2013
King's College London
2013
National Institute for Medical Research
2012
Centre for Genomic Regulation
2011
Medical Research Council
2011
Vrije Universiteit Amsterdam
2003-2005
Université de Lorraine
2000-2005
Centre National de la Recherche Scientifique
2000-2005
Cells of the spinal cord and somites arise from shared, dual-fated precursors, located towards posterior elongating embryo. Here we show that these neuromesodermal progenitors (NMPs) can readily be generated in vitro mouse human pluripotent stem cells by activating Wnt Fgf signalling, timed to emulate vivo development. Similar NMPs vivo, co-express neural factor Sox2 mesodermal Brachyury differentiate into paraxial mesoderm vivo. The produced have but not anterior identity motor neurons....
Highlights•Single-cell RNA-seq reveals a signature of neuromesodermal progenitors•In vitro NMPs resemble and differentiate similar to their in vivo counterparts•Dual role for retinoic acid signaling NMP induction neural differentiation•A transcriptional network regulates versus mesodermal allocationSummaryTranscriptional networks, regulated by extracellular signals, control cell fate decisions determine the size composition developing tissues. One example is controlling bipotent progenitors...
Neural crest rules the gut The neurons and glial cells that regulate function derive from neural emerge developing tube. Lasrado et al. used single-cell transcriptomics mosaic mutagenesis to follow how enteric nervous system is built in mice. Overlapping expression of regulatory programs supports dynamic determination cell fates, with organized by clonal lineages. build model may explain motility coordinated sequential segments secretion motility. Science , this issue p. 722
Abstract Glial cells have been proposed as a source of neural progenitors, but the mechanisms underpinning neurogenic potential adult glia are not known. Using single cell transcriptomic profiling, we show that enteric glial represent state attained by autonomic crest they transition along linear differentiation trajectory allows them to retain while acquiring mature functions. Key loci in early nervous system progenitors remain open chromatin configuration glia, thus facilitating neuronal...
Allostery offers a highly specific way to modulate protein function. Therefore, understanding this mechanism is of increasing interest for science and drug discovery. However, allosteric signal transmission difficult detect experimentally model because it often mediated by local structural changes propagating along multiple pathways. To address this, we developed method identify communication pathways an information-theoretical analysis molecular dynamics simulations. Signal propagation was...
Abstract Background The hierarchical and partially redundant nature of protein structures justifies the definition frequently occurring conformations short fragments as 'states'. Collections selected representatives for these states define Structural Alphabets, describing most typical local within structures. These alphabets form a bridge between string-oriented methods sequence analysis coordinate-oriented structure analysis. Results A Alphabet has been derived by clustering all...
Abstract Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia-inducible factor 1α (HIF1α) and necessary for cancer cell survival. However, the mechanisms that enable cells adapt early hypoxia, before HIF1α-mediated transcription programme is fully established, remain poorly understood. Here we show human breast cells, within 3 h of exposure, glycolytic flux increases a HIF1α-independent manner but limited NAD + availability. Glycolytic...
Allosteric regulation is crucial for biological processes like signal transduction, transcriptional regulation, and metabolism, yet the mechanisms macromolecular properties that govern it are still not well understood. Several methods have been developed over years to study allosterism through different angles. Among possible ways allosterism, information-theoretic approaches, AlloHubMat or GSAtools, can be particularly effective due their use of robust statistics possibility combined with...
A novel form of acto-myosin regulation has been proposed in which polymerization new actin filaments regulates motility parasites the apicomplexan class protozoa. In vivo and vitro parasite F-actin is very short unstable, but structural basis details filament dynamics remain unknown. Here, we show that long can be obtained by polymerizing unlabeled rabbit skeletal (RS-actin) onto both ends rhodamine-phalloidin-stabilized Plasmodium falciparum I (Pf-actin) filaments. Following annealing,...
Abstract Motivation: GSATools is a free software package to analyze conformational ensembles and detect functional motions in proteins by means of structural alphabet. The integrates with the widely used GROMACS simulation can generate range graphical outputs. Three applications be supported: (i) investigation variability local structures; (ii) detection allosteric communication; (iii) identification regions that are critical for global motions. These analyses provide insights into dynamics...
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...
Large-scale analysis of biomolecular complexes reveals the functional network within cell. Computational methods are required to extract essential information from available data. The POPSCOMP server is designed calculate interaction surface between all components a given complex structure consisting proteins, DNA or RNA molecules. returns matrices and graphs area burial that can be used automatically annotate residues involved in formation, pinpoint conformational changes estimate molecular...
We study the tailoring of structured random graph ensembles to real networks, with objective generating precise and practical mathematical tools for quantifying comparing network topologies macroscopically, beyond level degree statistics.Our family can produce graphs any prescribed distribution degree-degree correlation function, its control parameters be calculated fully analytically, as a result we calculate (asymptotically) formulae entropies complexities, information-theoretic distances...
Prion diseases are fatal neurodegenerative characterized by the formation of β-rich oligomers and accumulation amyloid fibrillar deposits in central nervous system. Understanding conversion cellular prion protein into its polymeric conformers is fundamental to tackling early stages development diseases. In this paper, we have identified unfolding refolding steps critical a conformer for different constructs ovine molecular dynamics simulations. By combining our results with vitro...
Abstract Summary: Multiple sequence alignment is a frequently used technique for analyzing relationships. Compilation of large alignments computationally expensive, but processing time can be considerably reduced when the computational load distributed over many processors. Parallel functionality in form single-instruction multiple-data (SIMD) technology was implemented into multiple program Praline by using ‘message passing interface’ (MPI) routines. Over tested here, parallelized performed...
Abstract Motivation: Evaluating alternative multiple protein sequence alignments is an important unsolved problem in Biology. The most accurate way of doing this to use structural information. Unfortunately, methods require at least two structures be embedded the alignment, a condition rarely met when dealing with standard datasets. Result: We developed STRIKE, method that determines relative accuracy same sequences using single structure. validated our methodology on three commonly used...
M10 is the most C-terminal immunoglobulin (Ig) domain of giant protein titin and a frequent target disease-linked mutations. Currently, it only known muscle Ig able to interact with two alternative ligands-obscurin obscurin-like-1 (Obsl1)-in different sarcomeric subregions. Obscurin Obsl1 use their homologous N-terminal (O1 in obscurin OL1 Obsl1) bind mutually exclusive manner. We present here X-ray structure human titin:obscurin M10:O1 complex extending our previous work on M10:OL1...
We apply our recently developed information-theoretic measures for the characterisation and comparison of protein–protein interaction networks. These are used to quantify topological network features via macroscopic statistical properties. Network differences assessed based on these properties as opposed microscopic overlap, homology information or motif occurrences. present results a large–scale analysis Precise null models in analyses, allowing reliable interpretation results. By...
To uncover the structural and dynamical determinants involved in highly specific binding of Ras GTPase to its effectors, conformational states uncomplexed form complexed downstream effectors Byr2, PI3Kγ, PLCε, RalGDS were investigated using molecular dynamics cross-comparison trajectories. The subtle changes conformations upon effector require an analysis that targets local independent global motions. Using a alphabet, computational procedure is proposed quantify changes. Positions detected...
Implicit solvation is a mean force approach to model solvent forces acting on solute molecule. It frequently used in molecular simulations reduce the computational cost of treatment. In first instance, free energy and associated solvent-solute can be approximated by function solvent-accessible surface area (SASA) differentiated an atom-specific parameter σ(i) (SASA). A procedure for determination values parameters through matching explicit implicit proposed. Using results Molecular Dynamics...
Inhibiting MAPK14 (p38α) diminishes cardiac damage in myocardial ischemia. During ischemia, p38α interacts with TAB1, a scaffold protein, which promotes autoactivation; active (pp38α) then transphosphorylates TAB1. Previously, we solved the X-ray structure of p38α-TAB1 (residues 384-412) complex. Here, further characterize interaction by solving pp38α-TAB1 1-438) complex state. Based on this information, created global knock-in (KI) mouse substitution 4 residues TAB1 that show are required...