A5053523332- Protein Structure and Dynamics
- Monoclonal and Polyclonal Antibodies Research
- Alzheimer's disease research and treatments
- Protein purification and stability
- Enzyme Structure and Function
- Prion Diseases and Protein Misfolding
- Viral Infectious Diseases and Gene Expression in Insects
- Receptor Mechanisms and Signaling
- Heat shock proteins research
- RNA Research and Splicing
- Neuropeptides and Animal Physiology
- Bacterial Genetics and Biotechnology
- COVID-19 Clinical Research Studies
- Glycosylation and Glycoproteins Research
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Molecular spectroscopy and chirality
- SARS-CoV-2 and COVID-19 Research
- RNA and protein synthesis mechanisms
- interferon and immune responses
- Protein Kinase Regulation and GTPase Signaling
- T-cell and B-cell Immunology
- Biosimilars and Bioanalytical Methods
- Transgenic Plants and Applications
- Escherichia coli research studies
VIB-KU Leuven Center for Brain & Disease Research
2016-2025
KU Leuven
2016-2025
Rega Institute for Medical Research
2024
VIB-KU Leuven Center for Microbiology
2022
Vlaams Instituut voor Biotechnologie
2016
Radboud University Nijmegen
2013-2014
Radboud University Medical Center
2013-2014
University of Copenhagen
2013
Bio-Prodict (Netherlands)
2013
For the past 20 years, GPCRDB (G protein-coupled receptors database; http://www.gpcr.org/7tm/) has been a 'one-stop shop' for G receptor (GPCR)-related data. The contains experimental data on sequences, ligand-binding constants, mutations and oligomers, as well many different types of computationally derived data, such multiple sequence alignments homology models. also provides visualization analysis tools, plus number query systems. In latest release, all alignments, >65 000 models, have...
Protein aggregation remains a major area of focus in the production monoclonal antibodies. Improving intrinsic properties antibodies can improve manufacturability, attrition rates, safety, formulation, titers, immunogenicity, and solubility. Here, we explore potential predicting reducing propensity antibodies, based on identification aggregation-prone regions their contribution to thermodynamic stability protein. Although are thought occur antigen binding region drive hydrophobic with...
Abstract Natural selection shapes protein solubility to physiological requirements and recombinant applications that require higher concentrations are often problematic. This raises the question whether of natural sequences can be improved. We here show an anti-correlation between number aggregation prone regions (APRs) in a sequence its solubility, suggesting mutational suppression APRs provides simple strategy increase solubility. mutations at specific positions within structure act as APR...
Protein aggregation is a major factor limiting the biotechnological and therapeutic application of many proteins, including enzymes monoclonal antibodies. The molecular principles underlying are by now sufficiently understood to allow rational redesign natural polypeptide sequences for decreased tendency, hence potentially increased expression solubility. Given that aggregation-prone regions (APRs) tend contribute stability hydrophobic core or functional sites protein, mutations in these...
Highlights•Mutations in the globular and amyloid state are thermodynamically correlated•The genetic code tightens this relationship between native state•Strongly amyloidogenic sequences proteins deeply conserved•Positive selection of propensity will favor protein stabilitySummaryThe amyloid-like aggregation present most is generally considered to be a secondary side effect resulting from requirements stability. Here, we demonstrate, however, that mutations correlated rather than simply...
Abstract Developing antibodies is complex and resource-intensive, methods for designing targeting specific epitopes are lacking. We introduce a de novo antibody design approach leveraging the empirical force field FoldX to complementarity determining regions (CDRs). Starting from scaffold VHH, we tackled three challenges of increasing difficulty: 1) CDRs optimize VHH stability affinity its original target; 2) high human ortholog; 3) low nanomolar pre-defined epitope on unrelated...
BackgroundThe molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% patients. SEC61A1 encodes the α-subunit Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations were reported be pathogenic common variable immunodeficiency glomerulocystic kidney disease.ObjectiveOur aim was expand spectrum SEC61A1-mediated disease include autosomal dominant SCN.MethodsWhole exome sequencing findings validated, compared...
Abstract Human amyloids have been shown to interact with viruses and interfere viral replication. Based on this observation, we employed a synthetic biology approach in which engineered virus-specific against influenza A Zika proteins. Each amyloid shares homologous aggregation-prone fragment specific target protein. For demonstrate that designer PB2 accumulates A-infected tissue vivo. Moreover, acts specifically its common polymorphisms, but not B, lacks the fragment. Our model demonstrates...
The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or CD8 dimeric IL2RBG receptor, respectively. However, utility IL2 treatment is limited by this same pleiotropy, protein engineering bias specificity towards either Treg lineage often requires trade-off in production total bioactivity. Here we use SolubiS dTANGO,...
Agonist binding is related to a series of motions in G protein-coupled receptors (GPCRs) that result the separation transmembrane helices III and VI at their cytosolic ends subsequent protein binding. A large number smaller also seem be associated with activation. Most GPCRs are highly irregular often contain kinks, extensive literature already available about role prolines kink formation precise function these kinks. GPCR many α-bulges. In this article we aim draw attention α-bulges ligand...
The FoldX force field was originally validated with a database of 1000 mutants at time when there were few high-resolution structures. Here we have manually curated 5556 affecting protein stability, resulting in 2484 highly confident mutations denominated Stability Dataset (FSD), represented non-redundant X-ray structures less than 2.5 Å resolution, not involving duplicates, metals or prosthetic groups. Using this database, created new version the by introducing Pi stacking, pH dependency...
Amyloid polymorphism is emerging as a key property that differentially linked to various conformational diseases, including major neurodegenerative disorders, but also feature potentially relates complex structural mechanisms mediating transmissibility barriers and selective vulnerability of amyloids. In response the rapidly expanding number amyloid fibril structures formed by full-length proteins, we here have developed StAmP-DB, public database supports curation cross-comparison...
Mutant KRAS is a major driver of oncogenesis in multitude cancers but remains challenging target for classical small molecule drugs, motivating the exploration alternative approaches. Here, we show that aggregation-prone regions (APRs) primary sequence oncoprotein constitute intrinsic vulnerabilities can be exploited to misfold into protein aggregates. Conveniently, this propensity present wild-type increased common oncogenic mutations at positions 12 and 13. We synthetic peptides...
Abstract Motivation: Protein aggregation is associated with a number of protein misfolding diseases and major concern for therapeutic proteins. Aggregation caused by the presence aggregation-prone regions (APRs) in amino acid sequence protein. The lower propensity APRs better they are protected native interactions within folded structure protein, more prevented. Therefore, both local thermodynamic stability their intrinsic key parameter that needs to be optimized prevent aggregation....
Aggregation of initially stably structured proteins is involved in more than 20 human amyloid diseases. Despite intense research, however, how this class assembles into fibrils remains poorly understood, principally because the complex effects amino acid substitutions on protein stability, solubility, and aggregation propensity. We address question using β2-microglobulin (β2m) as a model system, focusing D76N-β2m that hereditary amyloidosis. This substitution causes aggregation-resilient...
Abstract Monoclonal antibodies bind with high specificity to a wide range of diverse antigens, primarily mediated by their hypervariable complementarity determining regions (CDRs). The defined antigen binding loops are supported the structurally conserved β-sandwich framework light chain (LC) and heavy (HC) variable regions. LC genes encoded two separate loci, subdividing entity into kappa (LCκ) lambda (LCλ) isotypes that exhibit distinct sequence conformational preferences. In this work,...
Abstract The increasing amount of amyloid structures offers an opportunity to investigate the general principles determining stability and polymorphism in disease. We find that is dominated by about 30% residues localized few segments interspersed with regions are often structurally frustrated cross-β conformation. These stable correspond known aggregation-nucleating constitute a structural framework shared among polymorphs. Alternative tertiary packing these within protofibril results...
We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium January 2021. This variant, featuring a 3-amino acid insertion spike protein similar to Omicron was speculated enhance transmissibility or immune evasion. Initially detected international travelers, it substantially transmitted Central Africa, Belgium, Switzerland, France, peaking April Our travel-aware phylogeographic analysis, incorporating travel history,...
Abstract The accumulation of toxic protein aggregates is thought to play a key role in range degenerative pathologies, but it remains unclear why aggregation polypeptides into non-native assemblies and cellular clearance pathways offer ineffective protection. We here study the A4V mutant SOD1, which forms motor neurons patients with familial amyotrophic lateral sclerosis (ALS). A comparison location prone regions (APRs) Hsp70 binding sites denatured state SOD1 reveals that ALS-associated...
<title>Abstract</title> We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium January 2021. This variant, featuring a 3-amino acid insertion spike protein similar to Omicron was speculated enhance transmissibility or immune evasion. Initially detected international travelers, it substantially transmitted Central Africa, Belgium, Switzerland, France, peaking April Our travel-aware phylogeographic analysis, incorporating...