A5047090367- Cell Adhesion Molecules Research
- Protease and Inhibitor Mechanisms
- Connective tissue disorders research
- Glycosylation and Glycoproteins Research
- Proteoglycans and glycosaminoglycans research
- TGF-β signaling in diseases
- Ubiquitin and proteasome pathways
- Monoclonal and Polyclonal Antibodies Research
- Protein Structure and Dynamics
- Muscle metabolism and nutrition
- Cellular Mechanics and Interactions
- Protein Degradation and Inhibitors
- Lipid Membrane Structure and Behavior
- Chemokine receptors and signaling
- Enzyme Structure and Function
- Renal Diseases and Glomerulopathies
- Complement system in diseases
- Biomarkers in Disease Mechanisms
- ATP Synthase and ATPases Research
- Multiple Myeloma Research and Treatments
- Biochemical and Structural Characterization
- DNA Repair Mechanisms
- Developmental Biology and Gene Regulation
- Photosynthetic Processes and Mechanisms
- Biochemical and Molecular Research
University of Manchester
2016-2025
Wellcome Centre for Cell-Matrix Research
2015-2025
Manchester Academic Health Science Centre
2017-2025
Royal Perth Hospital
2022
Henry Royce Institute
2019
A number of short peptide amphiphiles consisting dipeptides linked to fluorenylmethoxycarbonyl spontaneously form fibrous hydrogels under physiological conditions (see figure). The structural and physical properties these gels are dictated by the amino acid sequence building blocks, support three-dimensional cell culture chondrocytes.
Phospholipase A2 receptor 1 (PLA2R) is a target autoantigen in 70% of patients with idiopathic membranous nephropathy. We describe the location major epitope N-terminal cysteine-rich ricin domain PLA2R that recognized by 90% human anti-PLA2R autoantibodies. The was sensitive to reduction and SDS denaturation isolated larger fragment containing ricin, fibronectin type II, first second C-type lectin domains (CTLD). However, nondenaturing conditions protected against fragments, including...
Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for complement regulator factor H (FH), a Tyr-to-His substitution at position 402, is linked to ∼50% attributable risks AMD. We present crystal structure region FH containing polymorphic amino acid His402 complex with an analogue glycosaminoglycans (GAGs) that localize on cell surface. The demonstrates direct...
Abstract TNF-stimulated gene/protein-6 (TSG-6) is expressed by many different cell types in response to proinflammatory cytokines and plays an important role the protection of tissues from damaging consequences acute inflammation. Recently, TSG-6 was identified as being largely responsible for beneficial effects multipotent mesenchymal stem cells, example treatment animal models myocardial infarction corneal injury/allogenic transplant. The protective effect due part its inhibition...
Graphene-based materials have shown significant potential for biomedical applications including biosensors, cell scaffolds and drug delivery. However, the interaction of complex biomacromolecules like proteins with graphene its derivatives, oxide (GO) reduced (r)GO, remains poorly understood. Here, we demonstrate that quartz-crystal microbalance dissipation monitoring (QCM-D) technique can be used to systematically study dynamics a typical protein, bovine serum albumin (BSA), varying degrees...
Our understanding of the activity cationic antimicrobial peptides (AMPs) has focused on well-characterized natural sequences, or limited sets synthetic designed de novo. We have undertaken a comprehensive investigation underlying primary structural features that give rise to development in AMPs. consider complete set all possible peptides, up 7 residues long, composed positively charged arginine (R) and / hydrophobic tryptophan (W), two most commonly associated with activity. found shortest...
Leukocyte recruitment from the vasculature into tissues is a crucial component of immune system but also key to inflammatory disease. Chemokines are central this process have yet be therapeutically targeted during inflammation due lack mechanistic understanding. Specifically, CXCL4 (Platelet Factor 4, PF4) has no established receptor that explains its function. Here, we use biophysical, in vitro, and vivo techniques determine mechanism underlying CXCL4-mediated leukocyte recruitment. We...
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 report the crystal structure of a thermophilic "ene" reductase (TOYE) isolated from Thermoanaerobacter pseudethanolicus E39. The reveals tetrameric enzyme and an active site that is relatively large compared to most other structurally determined related Old Yellow Enzymes. adopts higher order oligomeric states (octamers dodecamers) in solution, as revealed by sedimentation velocity multiangle laser light scattering. Bead modelling indicates solution consistent with basic observed...
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...
Infection by soil transmitted parasitic helminths, such as Trichuris spp, are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections poorly understood. Here we show that p43, single most abundant protein T. muris excretions/secretions, is non-immunogenic during infection has an unusual sequence structure containing subdomain homology to thrombospondin type 1 interleukin (IL)-13 receptor (R) α2. Binding p43 IL-13, key effector cytokine responsible...
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...
Coiled coils are extensively and successfully used nowadays to rationally design multistranded structures for applications, including basic research, biotechnology, nanotechnology, materials science, medicine. The wide range of applications as well the important functions these play in almost all biological processes highlight need a detailed understanding factors that control coiled-coil folding oligomerization. Here, we address unresolved question why presence particular...
Anterior gradient 2 (AGR2) is a normal endoplasmic reticulum protein that has two important abnormal functions, amphibian limb regeneration and human cancer metastasis promotion. These intracellular extracellular roles can be attributed to the multidomain structure of AGR2. The NMR shows AGR2 consists an unstructured N-terminal region followed by thioredoxin fold. exists in monomer–dimer equilibrium with Kd 8.83 μM, intermolecular salt bridges involving E60 K64 within folded domain serve...
Chemokine-driven leukocyte recruitment is a key component of the immune response and various diseases. Therapeutically targeting chemokine system in inflammatory disease has been unsuccessful, which attributed to redundancy. We investigated why chemokines instead have specific, specialized functions, as demonstrated by multiple studies. analyzed expression genes encoding their receptors across species, tissues, This analysis revealed complex patterns such that mediated same type were...
Cleft lip and cleft palate (CLP) are common disorders that occur either as part of a syndrome, where structures other than the affected, or in absence anomalies. Van der Woude syndrome (VWS) popliteal pterygium (PPS) autosomal dominant characterized by combinations lip, CLP, pits, skin-folds, syndactyly oral adhesions which arise result mutations interferon regulatory factor 6 (IRF6). IRF6 belongs to family transcription factors share highly conserved N-terminal, DNA-binding domain less...
Fibrillin-1 N- and C-terminal heparin binding sites have been characterized. An unprocessed monomeric N-terminal fragment (PF1) induced a very high response, indicating heparin-mediated multimerization. Using PF1 deletion short fragments, site was localized within the domain encoded by exon 7 after first hybrid domain. Rodent embryonic fibroblasts adhered to and, when cells were plated on fibrillin-1 or fibronectin Arg-Gly-Asp cell-binding showed heparin-dependent spreading focal contact...
The mechanical properties of the cell nucleus change to allow cells migrate, but how chromatin modifications contribute nuclear deformability has not been defined. Here, we demonstrate that a major factor in this process involves epigenetic changes underpin structure. We investigated link between adhesion and T-cells, T-cell VCAM1 via α4β1 integrin drives histone H3 methylation (H3K9me2/3) through methyltransferase G9a. In process, active G9a is recruited envelope interacts with lamin B1...
Significance We present here an entirely novel concept in the field of cell–cell adhesion, whereby flexibility extracellular domains cadherin molecules determines characteristics and behavior intercellular junctions. The structure ectodomain desmosomal desmoglein 2 shows it is flexible its calcium-bound form. This ectodomains may be key facilitating a unique property desmosomes: ability to switch from strong calcium-independent hyperadhesion adult tissues weaker calcium-dependent adhesion wounds.
Significance Bone morphogenetic proteins (BMPs) are essential signaling molecules important in embryo development and maintaining tissue function adulthood. BMPs regulated outside the cell by inhibitors such as chordin. The structure of chordin is unknown extracellular generally not suitable for high-resolution methods. This study uses electron microscopy other techniques to determine shape human It has a compact horseshoe-shaped with terminal BMP-binding regions protruding prongs. spacing...
We present a sensitive and low-cost immunoassay, based on customized open-source quartz crystal microbalance coupled with graphene biointerface sensors (G-QCM), to quantify antibodies in undiluted patient serum. demonstrate its efficacy for specific antibody against the phospholipase A2 receptor (anti-PLA2R), which is biomarker primary membranous nephropathy. A novel graphene–protein was constructed by adsorbing low concentration of denatured bovine serum albumin (dBSA) reduced oxide (rGO)...