A5061097943- Protein Structure and Dynamics
- SARS-CoV-2 and COVID-19 Research
- Alzheimer's disease research and treatments
- Monoclonal and Polyclonal Antibodies Research
- COVID-19 Clinical Research Studies
- Parkinson's Disease Mechanisms and Treatments
- Heat shock proteins research
- Protein purification and stability
- Microfluidic and Bio-sensing Technologies
- SARS-CoV-2 detection and testing
- RNA Research and Splicing
- Lipid Membrane Structure and Behavior
- S100 Proteins and Annexins
- RNA and protein synthesis mechanisms
- Computational Drug Discovery Methods
- Renal Transplantation Outcomes and Treatments
- Birth, Development, and Health
- Nuclear Structure and Function
- Biofuel production and bioconversion
- Receptor Mechanisms and Signaling
- Electromagnetic Fields and Biological Effects
- Advanced Fluorescence Microscopy Techniques
- Microfluidic and Capillary Electrophoresis Applications
- Supramolecular Self-Assembly in Materials
- Cellular transport and secretion
University of Cambridge
2020-2025
Max Planck Institute of Biochemistry
2024
Article26 July 2021Open Access Source DataTransparent process LAG3 is not expressed in human and murine neurons does modulate α-synucleinopathies Marc Emmenegger orcid.org/0000-0002-6073-8811 Institute of Neuropathology, University Zurich, Switzerland These authors contributed equally to this work Search for more papers by author Elena De Cecco orcid.org/0000-0002-0148-2596 Marian Hruska-Plochan orcid.org/0000-0002-9253-4362 Department Quantitative Biomedicine, Timo Eninger German Center...
Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo folding and preventing amyloid formation. Chaperones Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson's disease. However, mechanisms kinetics this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical study disaggregation. We show that Hsc70...
Abstract Segments of proteins with high β-strand propensity can self-associate to form amyloid fibrils implicated in many diseases. We describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide-binding clefts. The designs their cognate peptides vitro nanomolar affinities. crystal structure protein−peptide complex is close the design model, NMR characterization reveals how cleft protected apo state. use binders...
The humoral immune response plays a key role in suppressing the pathogenesis of SARS-CoV-2. molecular determinants underlying neutralization virus remain, however, incompletely understood. Here, we show that ability antibodies to disrupt binding viral spike protein angiotensin-converting enzyme 2 (ACE2) receptor on cell, event initiating SARS-CoV-2 entry into host cells, is controlled by affinity these antigen. By using microfluidic antibody-affinity profiling, were able quantify...
Antibody profiling is a fundamental component of understanding the humoral response in wide range disease areas. Most currently used approaches operate by capturing antibodies onto functionalised surfaces. Such measurements surface binding are governed an overall antibody titre, while two molecular parameters, affinity and concentration, challenging to determine individually from such approaches. Here, applying microfluidic diffusional sizing (MDS), we show how can overcome this challenge...
Nonspecific interactions are a key challenge in the successful development of therapeutic antibodies. The tendency for nonspecific binding antibodies is often difficult to reduce by rational design, and instead, it necessary rely on comprehensive screening campaigns. To address this issue, we performed systematic analysis impact surface patch properties antibody nonspecificity using designer library as model system single-stranded DNA ligand. Using an in-solution microfluidic approach, find...
Abstract Effective public-health measures and vaccination campaigns against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response ectodomain receptor-binding domain spike protein as well nucleocapsid SARS-CoV-2. used TRABI for continuous seromonitoring hospital patients healthy blood donors (n=72’222) in canton Zurich from December 2019 2020 (pre-vaccine period). Seroprevalence...
Amyloid fibrils are ordered aggregates that a pathological hallmark of many neurodegenerative disorders including Alzheimer′s Disease and Parkinson′s Disease. The process amyloid formation involves complex cascade by which soluble monomeric protein converts to insoluble, (amyloid fibrils). Although inhibiting the aggregation pathway is key target for therapeutic development, heterogeneous collection aggregation-prone species formed in this process, oligomers, protofibrils fibrils, represent...
Abstract Thyroid hormones are produced by the thyroid gland and essential for regulating metabolism, growth development. Maintenance of circulating hormone levels within an appropriate range is thus a prerequisite health. In vivo, this objective is, at least in part, facilitated through extracellular storage depot thyroglobulin, glycoprotein precursor hormones, follicular lumen. The molecular basis how soluble thyroglobulin molecules form such dense assemblies remains elusive. Here, we...
The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration antiviral antibodies and their affinity targets. However, polyclonal antibody responses in plasma difficult measure. Here we used microfluidic profiling (MAAP) determine aggregate affinities concentrations anti-SARS-CoV-2 samples 42 seropositive individuals, 19 were healthy donors, 20 displayed mild symptoms, 3 critically ill. We found that dissociation...
Effective public health measures against SARS-CoV-2 require granular knowledge of population-level immune responses. We developed a Tripartite Automated Blood Immunoassay (TRABI) to assess the IgG response three proteins. used TRABI for continuous seromonitoring hospital patients and blood donors (n = 72′250) in canton Zurich from December 2019 2020 (pre-vaccine period). found that antibodies waned with half-life 75 days, whereas cumulative incidence rose 2.3% June 12.2% mid-December 2020. A...
Abstract The complex kinetics of disease-related amyloid aggregation proteins such as α-Synuclein (α-Syn) in Parkinson’s disease and Aβ42 Alzheimer’s include primary nucleation, fibril elongation secondary nucleation. latter can be a key accelerator the process. It has been demonstrated that chaperone domain BRICHOS interfere with nucleation process Aβ42. Here, we explore mechanism inhibition lung surfactant protein (proSP-C) against α-Syn formation. We determine 3D NMR structure an inactive...
Templating mechanism of S100A9 amyloids on Aβ fibrillar surfaces during amyloid co-aggregation process was revealed by synergy biophysical methods including charge detection mass spectrometry, microscopy, kinetic and microfluidic analyses.
Abstract Segments of proteins with β-strand propensity can self associate to form amyloid fibrils associated many diseases. These regions often adopt alternative structures in their folded states, or are intrinsically disordered solution, making it difficult generate binders inhibitors existing strategies. Here we describe a general approach bind such segments and β-hairpin conformations using de novo designed scaffolds that contain deep peptide binding clefts flanked by β-strands hydrogen...
Abstract α-Synuclein (α-syn) accumulates as insoluble amyloid but also forms soluble α-syn oligomers (αSOs), thought to be even more cytotoxic than fibrils. To detect and block the unwanted activities of these αSOs, we have raised 30 monoclonal antibodies (mAbs) against different ranging from unmodified αSOs species stabilized by lipid peroxidation products polyphenols, formed C-terminally truncated α-syn, multivalent display on capsid virus-like particles (cVLPs). While mAbs generally show...
The aggregation of the amyloid β (Aβ) peptide is one molecular hallmarks Alzheimer's disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies also reported presence intracellular assemblies. Because these aggregates might play a role in onset and progression AD, it important to investigate their possible origins at different locations cell along secretory pathway precursor protein, from which derived by proteolytic cleavage. Senile plaques found AD are...
Abstract The detection and characterisation of antibodies in human blood is a key for clinical diagnostics risk assessment autoimmunity, infectious diseases transplanta-tion. Antibody titre derived from immunoassays commonly used measure anti-body response, but this metric does not resolve readily the two fundamental properties solution, namely their affinity concentration. This difficulty originates fact that parameters describing binding interaction, ligand concentration, are convoluted...
Recent efforts in understanding the course and severity of SARS-CoV-2 infections have highlighted both potentially beneficial detrimental effects cross-reactive antibodies derived from memory immunity. Specifically, due to a significant degree sequence similarity between other members coronavirus family, B-cells that emerged previous with endemic human coronaviruses (HCoVs) could be reactivated upon encountering newly SARS-CoV-2, thus prompting production antibodies. Determining affinity...
Abstract IgE antibodies against the allergen Ara-h2 can cause life-threatening anaphylaxis upon exposure to peanuts. Desensitization strategies aim at inducing IgG responses which may compete with anaphylactogenic IgE. Here we assessed anti-Ara-h2 titers in an unselected cohort of 24,536 adult patients admitted a general hospital for disparate medical reasons. Surprisingly, (n=177) and pediatric (n=76) cystic fibrosis (pwCF) had IgG4, but not IgE, several peanut soybean allergens, yet did...
Direct combination of liquid chromatography with multidimensional post-column analysis through microfluidics for individual quantification biophysical parameters.
Abstract The clinical outcome of SARS-CoV-2 infections, which can range from asymptomatic to lethal, is crucially shaped by the concentration antiviral antibodies and their affinity targets. However, polyclonal antibody responses in plasma difficult measure. Here we used Microfluidic Antibody Affinity Profiling (MAAP) determine aggregate affinities concentrations anti-SARS-CoV-2 samples 42 seropositive individuals, 19 were healthy donors, 20 displayed mild symptoms, 3 critically ill. We...