A5078032301- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Parkinson's Disease Mechanisms and Treatments
- Prion Diseases and Protein Misfolding
- Bacteriophages and microbial interactions
- Enzyme Structure and Function
- Bacterial Genetics and Biotechnology
- Mitochondrial Function and Pathology
- Receptor Mechanisms and Signaling
- Endoplasmic Reticulum Stress and Disease
- Protein Kinase Regulation and GTPase Signaling
- 14-3-3 protein interactions
- Neuropeptides and Animal Physiology
- Cholinesterase and Neurodegenerative Diseases
- Respiratory viral infections research
- Connective tissue disorders research
- Trace Elements in Health
- Supramolecular Self-Assembly in Materials
- Iron Metabolism and Disorders
- Nuclear Receptors and Signaling
- Monoclonal and Polyclonal Antibodies Research
- Photosynthetic Processes and Mechanisms
- Glycosylation and Glycoproteins Research
- Antimicrobial Resistance in Staphylococcus
University of Leeds
2020-2023
Universidad Autónoma del Estado de Morelos
2014-2023
Institute of Structural and Molecular Biology
2020-2022
Institut de Biologie Structurale
2018-2019
Centre National de la Recherche Scientifique
2018
CEA Grenoble
2018
Commissariat à l'Énergie Atomique et aux Énergies Alternatives
2018
Université Grenoble Alpes
2018
Centre for Biomedical Network Research on Rare Diseases
2013
Instituto de Salud Carlos III
1995-2013
Human islet amyloid polypeptide (hIAPP) self-assembles into fibrils which deposit in pancreatic islets of type 2 diabetes (T2D) patients. Here, we applied chemical kinetics to study the mechanism assembly wild-type hIAPP and its more amyloidogenic natural variant S20G. We show that aggregation both peptides involves primary nucleation, secondary nucleation elongation. also report discovery two structurally distinct small-molecule modulators assembly, one delaying wt hIAPP, but not S20G;...
Abstract Alpha-synuclein (αSyn) is a protein involved in neurodegenerative disorders including Parkinson’s disease. Amyloid formation of αSyn can be modulated by the ‘P1 region’ (residues 36-42). Here, mutational studies P1 reveal that Y39A and S42A extend lag-phase amyloid vitro rescue amyloid-associated cytotoxicity C. elegans . Additionally, L38I forms fibrils more rapidly than WT, L38A has no effect, but L38M does not form protects from proteotoxicity. Swapping sequence two residues...
To investigate whether negatively charged residues of the human Y1 neuropeptide Y (NPY) receptor are required for ligand binding, a series mutants were constructed in which aspartic acid and glutamic present putative extracellular domains systematically replaced by alanines. The mutant cDNAs transiently expressed HeLa cells using vaccinia virus-derived expression system, their ability to bind NPY was evaluated. level unable also tested immunologically. In addition, proteins be recruited cell...
β2-microglobulin (β2m) and its truncated variant ΔΝ6 are co-deposited in amyloid fibrils the joints, causing disorder dialysis-related amyloidosis (DRA). Point mutations of β2m result diseases with distinct pathologies. β2m-D76N causes a rare systemic protein deposited viscera absence renal failure, whilst β2m-V27M is associated deposits forming predominantly tongue. Here we use cryoEM to determine structures formed from these variants under identical conditions vitro. We show that each...
Summary Bacteria surround their cytoplasmic membrane with an essential, stress‐bearing peptidoglycan (PG) layer consisting of glycan chains linked by short peptides into a mesh‐like structure. Growing and dividing cells expand PG using inner‐membrane anchored synthases, including Penicillin‐binding proteins (PBPs), which participate in dynamic protein complexes to facilitate cell wall growth. In Escherichia coli , presumably other Gram‐negative bacteria, growth the mainly single layered is...
Peptidoglycan (PG) is an essential component of the cell envelope that maintains bacterial shape and protects it from bursting due to turgor pressure. The monoderm bacterium Staphylococcus aureus has a highly cross-linked PG with ~90% peptides stems participating in DD-cross-links up 15 peptide connected each other. These cross-links are formed transpeptidation reactions catalysed by Penicillin-binding proteins (PBPs) classes A B. Most S. strains have three housekeeping PBPs this function...
To determine which human respiratory syncytial virus (HRSV) P protein serine residues are modified by cellular kinase(s), several mutated versions of were expressed in the absence other viral proteins. Mutations at serines 232 or and 237 drastically reduced extent phosphorylation vivo. Serine is main site modification also essential for vitro casein kinase II. Additional vivo was detected region containing 116, 117 119.
Mutations in the ATP6 gene are reported to be associated with Leber hereditary optic neuropathy, bilateral striatal necrosis, coronary atherosclerosis risk and ataxia retinitis pigmentosa (NARP)/maternally inherited Leigh syndromes. Here, we present a patient NARP syndrome, whom previously undescribed mutation was detected gene: m.8839G>C. Several observations support concept that m.8839G>C is pathogenically involved clinical phenotype of this patient: (1) heteroplasmic muscle; (2) load...
Hereditary hyperferritinemia-cataract syndrome is a genetic condition characterized by constitutively increased serum ferritin values in the absence of iron overload and bilateral cataract. It has been demonstrated that mutations stem loop structure regulatory element (IRE) located 5'-untranslated region L-subunit gene (19q13.1) are responsible for anomalous expression this protein. Although not clearly explained, cataract formation seems secondary to levels lens. We analyzed large Basque...
Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, R24G mutation present 25% proteins germ AL patients. In work, five small molecules were tested inhibitors formation from 6aJL2-R24G protein. We have found thioflavin T fluorescence transmission electron microscopy that EGCG inhibits...
The D76N variant of human β2-microglobulin (β2m) is the causative agent a hereditary amyloid disease. Interestingly, D76N-associated amyloidosis has distinctive pathology compared with aggregation WT-β2m, which occurs in dialysis-related amyloidosis. A folding intermediate known as IT-state, contains nonnative trans Pro-32, been shown to be key precursor WT-β2m vitro However, how single amino acid substitution enhances rate D76N-β2m and gives rise different disease remained unclear. Using...
Light chain amyloidosis is the most common form of systemic amyloidosis. This disease caused by formation and deposition amyloid fibers made from immunoglobulin light chains. Environmental conditions such as pH temperature can affect protein structure induce development these fibers. Several studies have shed on native state, stability, dynamics, final state proteins; however, initiation process fibril pathway remain poorly understood structurally kinetically. To study this, we analyzed...
The pathological assembly of intrinsically disordered proteins/peptides (IDPs) into amyloid fibrils is associated with a range human pathologies, including neurodegeneration, metabolic diseases and systemic amyloidosis. These debilitating disorders affect hundreds millions people worldwide, the number affected increasing sharply. However, discovery therapeutic agents has been immensely challenging largely because (i) diverse aggregation pathways multi-conformational transient nature related...
Self-association of WT β2-microglobulin (WT-β2m) into amyloid fibrils is associated with the disorder dialysis related amyloidosis. In familial variant D76N-β2m, single amino acid substitution enhances aggregation propensity protein dramatically and gives rise to a that independent renal dysfunction. Numerous biophysical structural studies on WT- D76N-β2m have been performed in order better understand structure dynamics native proteins their different potentials aggregate amyloid. However,...
Light-chain amyloidosis (AL) is the most common systemic and caused by deposition of mainly insoluble immunoglobulin light chain amyloid fibrils in multiple organs, causing organ failure eventually death. The germ-line λ6a has been implicated AL, where a single point mutant at amino acid 24 (6aJL2-R24G) observed around 25% patient samples. Structural analysis shown only subtle differences between both proteins; nevertheless, 6aJL2-R24G more prone to form fibrils. To improve our understanding...