A5026197000- Alzheimer's disease research and treatments
- Protein Structure and Dynamics
- Prion Diseases and Protein Misfolding
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- Protein purification and stability
- Supramolecular Self-Assembly in Materials
- Cholinesterase and Neurodegenerative Diseases
- Antimicrobial Peptides and Activities
- Machine Learning in Bioinformatics
- Bacteriophages and microbial interactions
- 14-3-3 protein interactions
- Kruppel-like factors research
- interferon and immune responses
- Clusterin in disease pathology
- Heat shock proteins research
- Cell death mechanisms and regulation
- Protein Kinase Regulation and GTPase Signaling
- Microbial Natural Products and Biosynthesis
- Lipid Membrane Structure and Behavior
- Bacterial biofilms and quorum sensing
- Bioinformatics and Genomic Networks
- Biological Research and Disease Studies
- HIV Research and Treatment
- Inflammatory Bowel Disease
VIB-KU Leuven Center for Brain & Disease Research
2015-2025
KU Leuven
2014-2023
Vlaams Instituut voor Biotechnologie
2016
Switch
2014
Transition of soluble proteins into insoluble amyloid fibrils is driven by self-propagating short sequence stretches. However, accurate prediction aggregation determinants remains challenging. Here, we describe WALTZ-DB 2.0, an updated and significantly expanded open-access database providing information on experimentally determined amyloid-forming hexapeptide sequences (http://waltzdb.switchlab.org/). We have 2.0 with new entries, including: (i) experimental validation in-house developed...
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...
Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic peptide, based on an fragment of vascular endothelial growth factor receptor 2 (VEGFR2), protein that is not to amyloidosis. Vascin recapitulates key biophysical biochemical characteristics natural amyloids, penetrates cells, seeds the aggregation VEGFR2 through direct interaction....
Aggregation is a sequence-specific process, nucleated by short aggregation-prone regions (APRs) that can be exploited to induce aggregation of proteins containing the same APR. Here, we find most APRs are unique within proteome, but small minority occur in many proteins. When bacteria such frequently occurring APRs, it leads massive and lethal inclusion body formation large number Buildup bacterial resistance against these peptides slow. In addition, approach effective drug-resistant...
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...
Tauopathies encompass a group of neurodegenerative disorders characterised by diverse tau amyloid fibril structures. The persistence polymorphism across tauopathies suggests that distinct pathological conditions dictate the adopted polymorph for each disease. However, extent to which intrinsic structural tendencies cores contribute remains uncertain. Using combination experimental approaches, we here identify new amyloidogenic motif, PAM4 (Polymorphic Amyloid Motif Repeat 4), as significant...
Summary Taking advantage of the xenobiotic nature bacterial infections, we tested whether cytotoxicity protein aggregation can be targeted to pathogens without affecting their mammalian hosts. In particular, examined if peptides encoding aggregation‐prone sequence segments proteins display antimicrobial activity by initiating toxic in bacteria, but not cells. Unbiased vitro screening aggregating peptide sequences from genomes lead identification several that are strongly bactericidal against...
Cytoplasmic aggregation and nuclear depletion of TAR DNA-binding protein 43 (TDP-43) are hallmarks several neurodegenerative disorders. Yet, recapitulating both features in cellular systems has been challenging. Here, we produced amyloid-like fibrils from recombinant TDP-43 low-complexity domain demonstrate that sonicated trigger pathology human cells, including induced pluripotent stem cell (iPSC)-derived neurons. Fibril-induced cytoplasmic inclusions acquire distinct biophysical...
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...
Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic interactions, we no systematic understanding of the structural rules determining such nor whether they inhibit or facilitate assembly. Using structure-based thermodynamic calculations extensive experimental validation, performed a comprehensive exploration defining role promiscuity interactions. tau as model system...
Abstract Alzheimer’s disease is neuropathologically characterized by the deposition of amyloid β-peptide (Aβ) as plaques. Aβ plaque pathology starts in neocortex before it propagates into further brain regions. Moreover, aggregates undergo maturation indicated occurrence post-translational modifications. Here, we show that propagation plaques led presumably non-modified followed aggregate maturation. This sequence was seen human brains and precursor protein transgenic mice receiving...
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...
There is an arms race between beta-lactam antibiotics development and co-evolving beta-lactamases, which provide resistance by breaking down rings. We have observed that certain beta-lactamases tend to aggregate, persists throughout their evolution under the selective pressure of on active sites. Interestingly, we find existing beta-lactamase site inhibitors can act as molecular chaperones, promoting proper folding these factors. Therefore, created Pept-Ins, synthetic peptides designed...
Abstract In ulcerative colitis (UC) the butyrate metabolism is impaired, leading to energy‐deficiency in colonic cells. The effect of inflammation on was investigated. HT‐29 cells were incubated with pro‐inflammatory cytokines (TNF‐α and/or IFN‐γ) for 1 and 24 h. Cells additionally stimulated investigate its anti‐inflammatory potential. Butyrate uptake oxidation measured using 14 C‐labeled butyrate. Gene expression enzymes, interleukin 8 ( IL‐8 ; inflammatory marker) villin‐1 VIL‐1...
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...
Abstract Protein aggregation is an underappreciated mechanism that may contribute to the loss- and oncogenic-gain-of-function of mutant tumor suppressors such as p53 axin. In present study, we describe amyloid-like behaviour second most frequently mutated suppressor in human cancer, PTEN. silico analysis revealed a particularly high vulnerability for this protein, which was corroborated by vitro assays. cultured cells, found under stress conditions, PTEN readily undergoes result mutation....
Amyloid-like aggregation of proteins is induced by short amyloidogenic sequence segments within a specific protein resulting in self-assembly into β-sheets. We recently validated technology platform which synthetic amyloid peptides ("Pept-ins") containing aggregation-prone region (APR) are used to induce functional knockdown the target from APR was derived, including bacterial, viral, and mammalian cell proteins. In this work, we investigated if Pept-ins can be as vector probes for vivo...
Abstract Heterotypic amyloid interactions between related protein sequences have been observed in functional and disease amyloids. While sequence homology seems to favour heterotypic interactions, we no systematic understanding of the structural rules determining such nor whether they inhibit or facilitate assembly. Using structure-based thermodynamic calculations extensive experimental validation, performed a comprehensive exploration defining role promiscuity interactions. this knowledge,...
Abstract Different tauopathies are characterized by specific amyloid filament folds that conserved between patients. Disease-specific tau probably reflect the pathological contexts leading to their formation including isoforms or post-translational modifications. Little is known, however, as whether and how intrinsic conformational tendencies of sequence itself contribute its polymorphism. Using cryo-EM structure determination we find a short amyloidogenic C-terminal peptide consisting...