A5031768698- Cervical Cancer and HPV Research
- Protein Structure and Dynamics
- Cancer-related Molecular Pathways
- Hippo pathway signaling and YAP/TAZ
- Virus-based gene therapy research
- Hepatitis B Virus Studies
- Ubiquitin and proteasome pathways
- Molecular Biology Techniques and Applications
- 14-3-3 protein interactions
- S100 Proteins and Annexins
- Glycosylation and Glycoproteins Research
- interferon and immune responses
- Cancer-related gene regulation
- Protein Kinase Regulation and GTPase Signaling
- Bacteriophages and microbial interactions
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- Machine Learning in Bioinformatics
- Mitochondrial Function and Pathology
- Genomics and Phylogenetic Studies
- Cellular transport and secretion
- Protein purification and stability
- Genetic Neurodegenerative Diseases
- Advanced MRI Techniques and Applications
- Computational Drug Discovery Methods
Centre National de la Recherche Scientifique
2015-2024
Institut de génétique et de biologie moléculaire et cellulaire
2015-2024
Fraunhofer Institute for Interfacial Engineering and Biotechnology
2024
Inserm
1994-2024
Université de Strasbourg
2014-2024
Novo Nordisk (Denmark)
2024
Iowa State University
2024
Integrated Structural Biology Grenoble
2023
Institut de Biologie Moléculaire et Cellulaire
2006-2022
La Ligue Contre le Cancer
2020
E6 viral oncoproteins are key players in epithelial tumors induced by papillomaviruses vertebrates, including cervical cancer humans. proteins target many host specifically interacting with acidic LxxLL motifs. We solved the crystal structures of bovine (BPV1) and human (HPV16) papillomavirus bound to peptides from focal adhesion protein paxillin ubiquitin ligase E6AP, respectively. In both proteins, two zinc domains a linker helix form basic-hydrophobic pocket, which captures helical motifs...
Linear motifs are short segments of multidomain proteins that provide regulatory functions independently protein tertiary structure. Much intracellular signalling passes through modifications at linear motifs. Many thousands motif instances, most notably phosphorylation sites, have now been reported. Although clearly very abundant, difficult to predict de novo in sequences due the difficulty obtaining robust statistical assessments. The ELM resource http://elm.eu.org/ provides an expanding...
Abstract The seven 14-3-3 isoforms are highly abundant human proteins encoded by similar yet distinct genes. recognize phosphorylated motifs within numerous and viral proteins. Here, we analyze X-ray crystallography, fluorescence polarization, mutagenesis fusicoccin-mediated modulation the structural basis druggability of binding to four E6 oncoproteins tumorigenic papillomaviruses. bind variant mutated phospho-motifs unrelated protein RSK1 with different affinities, albeit following an...
Abstract Human protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here, we measure the of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection cancer. We calculate interactomic distances, identify hot spots...
Human Papillomavirus (HPV) E6 induced p53 degradation is thought to be an essential activity by which high-risk human Alphapapillomaviruses (alpha-HPVs) contribute cervical cancer development. However, most of our understanding derived from the comparison HPV16 and HPV11. These two viruses are relatively distinct viruses, making extrapolation these results difficult. In present study, we expand tested strains (types) include members all known HPV species groups within Alphapapillomavirus...
The HPV E6 oncoprotein maintains the malignant phenotype of HPV-positive cancer cells and represents an attractive therapeutic target. forms a complex with cellular E6AP ubiquitin ligase, ultimately leading to p53 degradation. recently elucidated x-ray structure HPV16 E6/E6AP showed that distinct binding pocket for E6AP. This discovery raises question whether is druggable, i. e. it provides docking site functional inhibitors. To address these issues, we performed detailed analysis...
The accurate description and subsequent modeling of protein interactomes require quantification their affinities at the proteome-wide scale. Here we develop validate Holdup Multiplex, a versatile assay with mass spectrometry (MS) readout for profiling large pools peptides. method can precisely quantify, in one single run, thousands affinity constants over several orders magnitude. throughput, dynamic range, sensitivity be pushed to performance limit MS readout. We applied Multiplex quantify...
Recombinant production of HPV oncoprotein E6 is notoriously difficult. The unfused sequence produced in inclusion bodies. By contrast, fusions to the C-terminus carrier proteins such as maltose-binding protein or gluthatione-S-transferase are soluble. However, it has not yet been possible purify from fusion constructs. Here, we show that this was due biophysical heterogeneity preparations. We find soluble MBP-E6 preparations contain two subpopulations. A major fraction aggregated and...
The E6 oncoprotein produced by high-risk mucosal HPV stimulates ubiquitinylation and proteasome-dependent degradation of the tumour suppressor p53 via formation a trimeric complex comprising E6, p53, E6-AP. is also degraded its main cellular regulator MDM2. binding site to MDM2 situated in natively unfolded N-terminal region p53. By contrast, regions implicated viral are not fully identified date. Here we generated series mutations (Y103G, Y107G, T155A, T155V, T155D, L264A, L265A) targeting...
PDZ domains recognise short sequence motifs at the extreme C-termini of proteins. A model based on microarray data has been recently published for predicting binding preferences to five residue long C-terminal sequences. Here we investigated potential this predictor discovering novel protein interactions that involve domains. When tested real negative assembled from literature, displayed a high false positive rate (FPR). We predicted and experimentally validated between four derived human...
Abstract Motivation: The phage display peptide selection approach is widely used for defining binding specificities of globular domains. PDZ domains recognize partner proteins via C-terminal motifs and are often as a model interaction predictions. Here, we investigated to which extent data that were recently published 54 human can be applied the prediction PDZ–peptide interactions. Results: Promising predictions obtained one-third For other two-thirds, detected in peptides an important bias...