A5058191684- RNA Research and Splicing
- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Amyotrophic Lateral Sclerosis Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Genetic and Kidney Cyst Diseases
- Oral microbiology and periodontitis research
- Computational Drug Discovery Methods
- Cancer-related gene regulation
- Cellular Mechanics and Interactions
- Protein purification and stability
- Enzyme Structure and Function
- Proteins in Food Systems
- Oral and Maxillofacial Pathology
- Neurogenetic and Muscular Disorders Research
- Lipid Membrane Structure and Behavior
- Cellular transport and secretion
- Prion Diseases and Protein Misfolding
- Amino Acid Enzymes and Metabolism
- Force Microscopy Techniques and Applications
- Innovative Microfluidic and Catalytic Techniques Innovation
- Vascular Malformations and Hemangiomas
- Microbial Metabolic Engineering and Bioproduction
University of Cambridge
2016-2025
Vinoba Bhave University
2020-2025
Creative Commons
2021
Government Dental College and Hospital
2021
Institute for Medical Research
2020
National Institute for Health Research
2015
Addenbrooke's Hospital
2005-2014
Wellcome Trust
2013-2014
Memorial Sloan Kettering Cancer Center
2000-2002
University of Leeds
1996-2000
The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS FTD remain controversial. We propose a model low-complexity (LC) domains of drive its physiologically reversible assembly into membrane-free, liquid droplet hydrogel-like structures. ALS/FTD LC or non-LC induce further phase transition poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary sufficient for neurotoxicity C. elegans FUS-dependent neurodegeneration....
Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles is, part, driven by intrinsically disordered low-complexity (LC) domain FUS. Here, we report that cooperative cation-π interactions between tyrosines LC arginines structured C-terminal domains also contribute to separation. These are modulated post-translational arginine methylation, wherein hypomethylation strongly promotes gelation. Indeed, significant hypomethylation,...
Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for in which granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), granule-associated phosphoinositide-binding protein,...
Abstract Liquid–liquid phase separation of proteins underpins the formation membraneless compartments in living cells. Elucidating molecular driving forces underlying protein transitions is therefore a key objective for understanding biological function and malfunction. Here we show that cellular proteins, which form condensates at low salt concentrations, including FUS, TDP-43, Brd4, Sox2, Annexin A11, can reenter phase-separated regime high concentrations. By bringing together experiments...
A wide range of macromolecules can undergo phase separation, forming biomolecular condensates in living cells. These membraneless organelles are typically highly dynamic, formed reversibly, and carry out essential functions biological systems. Crucially, however, a further liquid-to-solid transition the lead to irreversible pathological aggregation cellular dysfunction associated with onset development neurodegenerative diseases. Despite importance this proteins, mechanism by which it is...
Abstract The formation of biomolecular condensates through phase separation from proteins and nucleic acids is emerging as a spatial organisational principle used broadly by living cells. Many such are not, however, homogeneous fluids, but possess an internal structure consisting distinct sub-compartments with different compositions. Notably, can contain compartments that depleted in the biopolymers make up condensate. Here, we show double-emulsion emerge via dynamically arrested...
Research Article30 August 2017Open Access Source DataTransparent process TREM2 shedding by cleavage at the H157-S158 bond is accelerated for Alzheimer's disease-associated H157Y variant Peter Thornton Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Granta Park, Cambridge, UK Search more papers this author Jean Sevalle Tanz Centre in Neurodegenerative Diseases, University of Toronto, ON, Canada Michael J Deery Cambridge Proteomics, UKCorrection added on 2 October 2017...
The assembly of biomolecules into condensates is a fundamental process underlying the organisation intracellular space and regulation many cellular functions. Mapping characterising phase behaviour essential to understand mechanisms condensate assembly, develop therapeutic strategies targeting biomolecular systems. A central concept for phase-separating systems diagram. Phase diagrams are typically built from numerous individual measurements sampling different parts parameter space. However,...
Oligomers of the 40 and 42 residue amyloid-β peptides (Aβ40 Aβ42) have been implicated in neuronal damage impaired cognitive function associated with Alzheimer's disease. However, little is known about specific mechanisms by which these misfolded species induce such detrimental effects on cells. In this work, we use single-molecule imaging techniques to examine initial interactions between Aβ monomers oligomers membranes live This highly sensitive method enables visualization individual cell...
The molecular mechanism of protein aggregation is both fundamental and clinical importance as amyloid aggregates are linked to a number neurodegenerative disorders. Such include macroscopic insoluble fibrils well small soluble oligomeric species. Time-dependent resolution these species prerequisite for detailed quantitative understanding aggregation; this remains challenging due the lack methods detecting characterizing transient heterogeneous oligomers. Here we have used single molecule...
TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids Aβ inducing an innate immune response. Missense mutations (e.g., R47H) of increase risk Alzheimer's disease (AD). The soluble ectodomain wild-type (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that oligomers bind cellular TREM2, shedding sTREM2 domain. Wild-type bound (measured by single-molecule imaging, dot blots, Bio-Layer...
Abstract Introduction The second most common form of early‐onset dementia—frontotemporal dementia (FTD)—is often characterized by the aggregation microtubule‐associated protein tau. Here we studied mechanism tau‐induced neuronal dysfunction in neurons with FTD‐related 10+16 MAPT mutation. Methods Live imaging, electrophysiology, and redox proteomics were used induced pluripotent stem cell‐derived a model tau spreading primary cultures. Results Overproduction mitochondrial reactive oxygen...
Phase separation of biomolecules gives rise to membraneless organelles that contribute the spatiotemporal organization cell. In most cases, such biomolecular condensates contain multiple components, but manner in which interactions between components control stability have remained challenging elucidate. Here, we develop an approach determine tie-line gradients ternary phase-separation systems based on measurements dilute phase concentration only one component. We show sign gradient is...
Highlights•The head contains nicastrin ectodomain and overhangs a solute-accessible cavity in base•The base has central channel lateral cleft (putative substrate docking site)•Inhibitors close the rotate head, blocking accessSummaryPresenilin-mediated endoproteolysis of transmembrane proteins plays key role physiological signaling pathogenesis Alzheimer disease some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used...
Abstract Biomolecular phase separation plays a pivotal role in governing critical biological functions and arises from the collective interactions of large numbers molecules. Characterising underlying separation, however, has proven to be challenging with currently available tools. Here, we propose general easily accessible strategy quantify biomolecular respect composition energetics. By measuring dilute concentration one species only, determine tie line gradients free energy dominance as...
Oligomers of the amyloid-β peptide (Aβ) play a central role in pathogenesis Alzheimer's disease and have been suggested to induce neurotoxicity by binding plethora cell-surface receptors. However, heterogeneous mixtures oligomers varying sizes conformations formed Aβ42 obscured nature oligomeric species that bind given receptor. Here, we used single-molecule imaging characterize (oAβ42) confirm controversial interaction oAβ42 with cellular prion protein (PrP(C)) on live neuronal cells. Our...
The vacuolar-type ATPase (H + ATPase) is a ubiquitously expressed multisubunit pump whose regulation poorly understood. Its membrane-integral a-subunit involved in proton translocation and humans has four forms, a1–a4. This study investigated two naturally occurring point mutations a4's COOH terminus that cause recessive distal renal tubular acidosis (dRTA), R807Q G820R. Both lie within domain binds the glycolytic enzyme phosphofructokinase-1 (PFK-1). We recreated these disease yeast to...
Abstract Phase transitions of cellular proteins and lipids play a key role in governing the organisation coordination intracellular biology. Recent work has raised intriguing prospect that phase can be co-regulated. Here we investigate this possibility ribonucleoprotein (RNP) granule-ANXA11-lysosome ensemble, where ANXA11 tethers RNP granules to lysosomal membranes enable their co-trafficking. We show changes protein state within system, driven by low complexity N-terminus, induces coupled...