A5029876279- Connective tissue disorders research
- Protease and Inhibitor Mechanisms
- Cell Adhesion Molecules Research
- TGF-β signaling in diseases
- Collagen: Extraction and Characterization
- Cellular Mechanics and Interactions
- Bone and Dental Protein Studies
- Elasticity and Material Modeling
- Enzyme Structure and Function
- Protein Structure and Dynamics
- Cancer-related gene regulation
- Glycosylation and Glycoproteins Research
- Chemical Synthesis and Analysis
- Aortic aneurysm repair treatments
- Proteoglycans and glycosaminoglycans research
- Developmental Biology and Gene Regulation
- Blood properties and coagulation
- Biomarkers in Disease Mechanisms
- Tissue Engineering and Regenerative Medicine
- Antimicrobial agents and applications
- Carbohydrate Chemistry and Synthesis
- Protein purification and stability
- Biochemical and Molecular Research
- Skin and Cellular Biology Research
- Galectins and Cancer Biology
Manchester Academic Health Science Centre
2017-2025
University of Manchester
2016-2025
Wellcome Centre for Cell-Matrix Research
2016-2025
Henry Royce Institute
2018-2019
St George's, University of London
2010
University of Sheffield
1995-2003
Utrecht University
2001
St Thomas' Hospital
1993
British Museum
1993
University of Wales
1993
Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and front-line antituberculosis drug isoniazid. Analysis of structures complexes Escherichia coli ENR with nicotinamide adenine dinucleotide either thienodiazaborine or benzodiazaborine revealed formation a covalent bond between 2′ hydroxyl ribose boron atom drugs to generate tight, noncovalently bound bisubstrate analog. This analysis has implications structure-based design...
The ability of the cornea to transmit light while being mechanically resilient is directly attributable formation an extracellular matrix containing orthogonal sheets collagen fibrils. detailed structure fibrils and how this underpins mechanical properties organization understood poorly. In study, we used automated electron tomography study three-dimensional molecules in corneal reconstructions show that 36-nm diameter are organized into microfibrils (approximately 4-nm diameter) tilted by...
Elastin enables the reversible deformation of elastic tissues and can withstand decades repetitive forces. Tropoelastin is soluble precursor to elastin, main protein found in mammals. Little known shape mechanism assembly tropoelastin as its unique composition propensity self-associate has hampered structural studies. In this study, we solve nanostructure full-length corresponding overlapping fragments using small angle X-ray neutron scattering, allowing us identify discrete regions...
Control of the bioavailability growth factor TGFbeta is essential for tissue formation and homeostasis, yet precisely how latent incorporated into extracellular matrix unknown. Here, we show that deposition a large complex (LLC), which contains TGFbeta-binding protein 1 (LTBP-1), directly dependent on pericellular assembly fibrillin microfibrils, interact with fibronectin during higher-order fibrillogenesis. LTBP-1 formed arrays colocalized whereas knockdown inhibited fibrillar and/or LLC...
Pentraxin-3 (PTX3) is an octameric protein, comprised of eight identical protomers, that has diverse functions in reproductive biology, innate immunity and cancer. PTX3 interacts with the large polysaccharide hyaluronan (HA) to which heavy chains (HCs) inter-α-inhibitor (IαI) family proteoglycans are covalently attached, playing a key role (non-covalent) crosslinking HC•HA complexes. These interactions stabilise cumulus matrix, essential for ovulation fertilisation mammals, also implicated...
We propose a new model for the alignment of fibrillin molecules within microfibrils. Automated electron tomography was used to generate three-dimensional microfibril reconstructions 18.6-Å resolution, which revealed many organizational details untensioned microfibrils, including heart-shaped beads from two arms emerge, and interbead diameter variation. Antibody epitope mapping microfibrils juxtaposition epitopes at COOH terminus near proline-rich region, internal that would be 42-nm apart in...
The inflammation-associated long pentraxin PTX3 plays key roles in innate immunity, female fertility, and vascular biology (e.g. it inhibits FGF2 (fibroblast growth factor 2)-mediated angiogenesis). is composed of multiple protomers, each distinct N- C-terminal domains; however, not known how these are organized or contribute to its functional properties. Here, biophysical analyses reveal that eight identical associated through disulfide bonds, forming an elongated asymmetric, molecule with...
Fibulin-4 and -5 are extracellular glycoproteins with essential non-compensatory roles in elastic fiber assembly. We have determined how they interact tropoelastin, lysyl oxidase, fibrillin-1, thereby revealing differentially regulate Strong binding between fibulin-4 oxidase enhanced the interaction of forming ternary complexes that may direct elastin cross-linking. In contrast, fibulin-5 did not bind strongly but bound tropoelastin terminal central regions could concurrently fibulin-4. Both...
Lysyl oxidases (LOXs) play a central role in extracellular matrix remodeling during development and tumor growth fibrosis through cross-linking of collagens elastin. We have limited knowledge the structure substrate specificity these secreted enzymes. LOXs share conserved C-terminal catalytic domain but differ their N-terminal region, which is composed 4 repeats scavenger receptor cysteine-rich (SRCR) domains LOX-like (LOXL) 2. investigated by X-ray scattering electron microscopy...
Fibrillin-1 assembly into microfibrils and elastic fiber formation involves interactions with glycosaminoglycans. We have used BIAcore technology to investigate fibrillin-1 heparin saccharides that are analogous S-domains of heparan sulfate. identified four high affinity heparin-binding sites on fibrillin-1, localized three these sites, defined their binding kinetics. Heparin the N terminus has particularly rapid Hyaluronan chondroitin sulfate did not interact significantly fibrillin-1. more...
The extracellular glycoprotein fibrillin-1 forms microfibrils that act as the template for elastic fibers. Most mutations in cause Marfan syndrome with severe cardiovascular and ocular symptoms, tall stature. This is contrast to within a heparin-binding TB domain (TB5), which downstream of arg-gly-asp cell adhesion domain, can Weill-Marchesani (WMS) or Acromicric (AD) Geleophysic Dysplasias (GD). WMS characterized by short limbs, joint stiffness defects, whilst AD GD have stature, defects...