ETCHEBEST
@inserm.fr
Sciences Faculty Université de Paris
UMR-S1134
1982: CNRS Researcher, Theoretical Biochemistry Laboratory, IBPC, Paris.
1999-Present: Professor University Paris-Diderot, Biochemistry and Life Sciences Department.
1999-2005: Member of UMR-S726, “Genomics Bioinformatics and Molecular Modelling” (EBGM). Molecular Modelling group leader
2005-2008: Director of UMR-S726.
2009-2018: Team Leader of DSIMB, “Dynamic of Structures and Interactions of Macromolecules in Biology” UMR_S1134” Integrated Red Blood Cell Physiology. University Paris Diderot-Inserm and Institut National de la Transfusion Sanguine (INTS)
2019-Present: Leader of Molecular Modelling Group in DSIMB.
Responsibilities at the University and National Institutions.
2004-2008: Vice-President of the French Biophysical Society.
2014-2019: Vice President of French National Board of Universities (CNU) Section “Biochemistry and Molecular Biology”. This national board qualifies biochemists and molecular biologists for lecturer or professor positions, which is required before applying for positions in University.
2009- : Administration Council of Life Sciences Department in Paris-Diderot University (Elected member)
2018-2019: Research Commission of the Paris-Diderot University (Elected member).
2018-2019: President of Scientific Strategy and Evaluation commission of Paris-Diderot University
2019-2023: Administrative Board of Faculty of Sciences of “Université de Paris” (Elected member)
EDUCATION
1979 Maîtrise Physical-Chemistry (Eq. Bachelor Degree) Pierre et Marie Curie-Paris VI University
1980 DEA Physical-Chemistry (Eq. Master Degree) Pierre et Marie Curie-Paris VI University
1983 3rd Cycle Doctorate Physical-Chemistry (Eq. PhD) Pierre et Marie Curie-Paris VI University
1987 State Doctorate (Eq. Habilitation) Pierre et Marie Curie-Paris VI University
RESEARCH INTERESTS
Membrane Protein Systems, Molecular Mechanisms, Biophysics, Molecular Modelling, Structural Bioinformatics.
Scopus Publications
Scholar Citations
Scholar h-index
Scholar i10-index
Scopus Publications
Rajas M. Rao, Ibaa El Dhaybi, Frédéric Cadet, Catherine Etchebest, and Julien Diharce
Elsevier BV
Benoit Allegrini, Ludivine David NGuyen, Morgane Mignotet, Catherine Etchebest, Odile Fenneteau, Jessica Platon, Anne Lambilliotte, Hélène Guizouarn, and Lydie Da Costa
Elsevier BV
Stéphane Téletchéa, Jérémy Esque, Aurélie Urbain, Catherine Etchebest, and Alexandre G. de Brevern
MDPI AG
Transmembrane proteins (TMPs) are a class of essential proteins for biological and therapeutic purposes. Despite an increasing number of structures, the gap with the number of available sequences remains impressive. The choice of a dedicated function to select the most probable/relevant model among hundreds is a specific problem of TMPs. Indeed, the majority of approaches are mostly focused on globular proteins. We developed an alternative methodology to evaluate the quality of TMP structural models. HPMScore took into account sequence and local structural information using the unsupervised learning approach called hybrid protein model. The methodology was extensively evaluated on very different TMP all-α proteins. Structural models with different qualities were generated, from good to bad quality. HPMScore performed better than DOPE in recognizing good comparative models over more degenerated models, with a Top 1 of 46.9% against DOPE 40.1%, both giving the same result in 13.0%. When the alignments used are higher than 35%, HPM is the best for 52%, against 36% for DOPE (12% for both). These encouraging results need further improvement particularly when the sequence identity falls below 35%. An area of enhancement would be to train on a larger training set. A dedicated web server has been implemented and provided to the scientific community. It can be used with structural models generated from comparative modeling to deep learning approaches.
Akhila Melarkode Vattekatte, Julien Diharce, Joseph Rebehmed, Frédéric Cadet, Fabrice Gardebien, Catherine Etchebest, and Alexandre G. de Brevern
MDPI AG
Conformational flexibility plays an essential role in antibodies’ functional and structural stability. They facilitate and determine the strength of antigen–antibody interactions. Camelidae express an interesting subtype of single-chain antibody, named Heavy Chain only Antibody. They have only one N-terminal Variable domain (VHH) per chain, composed of Frameworks (FRs) and Complementarity Determining regions (CDRs) like their VH and VL counterparts in IgG. Even when expressed independently, VHH domains display excellent solubility and (thermo)stability, which helps them to retain their impressive interaction capabilities. Sequence and structural features of VHH domains contributing to these abilities have already been studied compared to classical antibodies. To have the broadest view and understand the changes in dynamics of these macromolecules, large-scale molecular dynamics simulations for a large number of non-redundant VHH structures have been performed for the first time. This analysis reveals the most prevalent movements in these domains. It reveals the four main classes of VHHs dynamics. Diverse local changes were observed in CDRs with various intensities. Similarly, different types of constraints were observed in CDRs, while FRs close to CDRs were sometimes primarily impacted. This study sheds light on the changes in flexibility in different regions of VHH that may impact their in silico design.
Cédric Vrignaud, Mahmoud Mikdar, Romain Duval, Luc Reininger, Vijaya L. Damaraju, Michael Sawyer, Yves Colin, Caroline Le Van Kim, Jean‐Christophe Gelly, Catherine Etchebest,et al.
Wiley
BACKGROUND
An antibody directed against a high-prevalence red blood cell (RBC) antigen was detected in a 67-year-old female patient of North African ancestry with a history of a single pregnancy and blood transfusion. So far, the specificity of the proband's alloantibody remained unknown in our immunohematology reference laboratory.
STUDY DESIGN AND METHODS
Whole-exome sequencing (WES) was performed on the proband's DNA. The reactivity to the SLC29A1-encoded ENT1 adenosine transporter was investigated by flow cytometry analyses of ENT1-expressing HEK293 cells, and RBCs from Augustine-typed individuals. Erythrocyte protein expression level, nucleoside-binding capacity, and molecular structure of the proband's ENT1 variant were further explored by western blot, flow cytometry, and molecular dynamics calculations, respectively.
RESULTS
A missense variant was identified in the SLC29A1 gene, which encodes the Augustine blood group system. It arises from homozygosity for a rare c.242A > G missense mutation that results in a nonsynonymous p.Asn81Ser substitution within the large extracellular loop of ENT1. Flow cytometry analyses demonstrated that the proband's antibody was reactive against HEK-293 cells transfected with control but not proband's SLC29A1 cDNA. Consistent with this finding, proband's antibody was found to be reactive with At(a-) (AUG:-2), but not AUG:-1 (null phenotype) RBCs. Data from structural analysis further supported that the proband's p.Asn81Ser variation does not alter ENT1 binding of its specific inhibitor NBMPR.
CONCLUSION
Our study provides evidence for a novel high-prevalence antigen, AUG4 (also called ATAM after the proband's name) in the Augustine blood group system, encoded by the rare SLC29A1 variant allele AUG*04 (c.242A > G, p.Asn81Ser).
Sergio Alejandro Poveda Cuevas, Fernando L. Barroso da Silva, and Catherine Etchebest
American Chemical Society (ACS)
Zika virus (ZIKV) from Uganda (UG) expresses a phenotype related to fetal loss, whereas the variant from Brazil (BR) induces microcephaly in neonates. The differential virulence has a direct relation to biomolecular mechanisms that make one strain more aggressive than the other. The nonstructural protein 1 (NS1) is a key viral toxin to comprehend these viral discrepancies because of its versatility in many processes of the virus life cycle. Here, we aim to examine through coarse-grained models and molecular dynamics simulations the protein-membrane interactions for both NS1ZIKV-UG and NS1ZIKV-BR dimers. A first evaluation allowed us to establish that the NS1 proteins, in the membrane presence, explore new conformational spaces when compared to systems simulated without a lipid bilayer. These events derive from both differential coupling patterns and discrepant binding affinities to the membrane. The N-terminal domain, intertwined loop, and greasy finger proposed previously as binding membrane regions were also computationally confirmed by us. The anchoring sites have aromatic and ionizable residues that manage the assembly of NS1 toward the membrane, especially for the Ugandan variant. Furthermore, in the presence of the membrane, the difference in the dynamic cross-correlation of residues between the two strains is particularly pronounced in the putative epitope regions. This suggests that the protein-membrane interaction induces changes in the distal part related to putative epitopes. Taken together, these results open up new strategies for the treatment of flaviviruses that would specifically target these dynamic differences.
David R. Gnimpieba Zanfack, Adam Bellaïche, Catherine Etchebest, Saurabh Dhiman, Venkataramana Gadhamshetty, Alain B. Bomgni, and Etienne Z. Gnimpieba
American Chemical Society
Aravindan Arun Nadaradjane, Julien Diharce, Joseph Rebehmed, Frédéric Cadet, Fabrice Gardebien, Jean-Christophe Gelly, Catherine Etchebest, and Alexandre G. de Brevern
Informa UK Limited
Heavy Chain Only Antibodies are specific to Camelid species. Despite the lack of the light chain variable domain, their heavy chain variable domain (VH) domain, named VHH or nanobody, has promising potential applications in research and therapeutic fields. The structural study of VHH is therefore of great interest. Unfortunately, considering the huge amount of sequences that might be produced, only about one thousand of VHH experimental structures are publicly available in the Protein Data Bank, implying that structural model prediction of VHH is a necessary alternative to obtaining 3D information besides its sequence. The present study aims to assess and compare the quality of predictions from different modelling methodologies. Established comparative & homology modelling approaches to recent Deep Learning-based modelling strategies were applied, i.e. Modeller using single or multiple structural templates, ModWeb, SwissModel (with two evaluation schema), RoseTTAfold, AlphaFold 2 and NanoNet. The prediction accuracy was evaluated using RMSD, TM-score, GDT-TS, GDT-HA and Protein Blocks distance metrics. Besides the global structure assessment, we performed specific analyses of Frameworks and CDRs structures. We observed that AlphaFold 2 and especially NanoNet performed better than the other evaluated softwares. Importantly, we performed molecular dynamics simulations of an experimental structure and a NanoNet predicted model of a VHH in order to compare the global structural flexibility and local conformations using Protein Blocks. Despite rather similar structures, substantial differences in dynamical properties were observed, which underlies the complexity of the task of model evaluation.Communicated by Ramaswamy H. Sarma.
Sergio A. Poveda-Cuevas, Catherine Etchebest, and Fernando L. Barroso da Silva
Elsevier BV
B. Allegrini, S. Jedele, L. David Nguyen, M. Mignotet, R. Rapetti-Mauss, C. Etchebest, O. Fenneteau, A. Loubat, A. Boutet, C. Thomas,et al.
Frontiers Media SA
The K+ channel activated by the Ca2+, KCNN4, has been shown to contribute to red blood cell dehydration in the rare hereditary hemolytic anemia, the dehydrated hereditary stomatocytosis. We report two de novo mutations on KCNN4, We reported two de novo mutations on KCNN4, V222L and H340N, characterized at the molecular, cellular and clinical levels. Whereas both mutations were shown to increase the calcium sensitivity of the K+ channel, leading to channel opening for lower calcium concentrations compared to WT KCNN4 channel, there was no obvious red blood cell dehydration in patients carrying one or the other mutation. The clinical phenotype was greatly different between carriers of the mutated gene ranging from severe anemia for one patient to a single episode of anemia for the other patient or no documented sign of anemia for the parents who also carried the mutation. These data compared to already published KCNN4 mutations question the role of KCNN4 gain-of-function mutations in hydration status and viability of red blood cells in bloodstream.
Poonam Vishwakarma, Akhila Melarkode Vattekatte, Nicolas Shinada, Julien Diharce, Carla Martins, Frédéric Cadet, Fabrice Gardebien, Catherine Etchebest, Aravindan Arun Nadaradjane, and Alexandre G. de Brevern
MDPI AG
VHH, i.e., VH domains of camelid single-chain antibodies, are very promising therapeutic agents due to their significant physicochemical advantages compared to classical mammalian antibodies. The number of experimentally solved VHH structures has significantly improved recently, which is of great help, because it offers the ability to directly work on 3D structures to humanise or improve them. Unfortunately, most VHHs do not have 3D structures. Thus, it is essential to find alternative ways to get structural information. The methods of structure prediction from the primary amino acid sequence appear essential to bypass this limitation. This review presents the most extensive overview of structure prediction methods applied for the 3D modelling of a given VHH sequence (a total of 21). Besides the historical overview, it aims at showing how model software programs have been shaping the structural predictions of VHHs. A brief explanation of each methodology is supplied, and pertinent examples of their usage are provided. Finally, we present a structure prediction case study of a recently solved VHH structure. According to some recent studies and the present analysis, AlphaFold 2 and NanoNet appear to be the best tools to predict a structural model of VHH from its sequence.
Jihane Akachar, Catherine Etchebest, Rachid El Jaoudi, and Azeddine Ibrahimi
Springer Science and Business Media LLC
AbstractThe transmembrane glycoprotein CD36, which is responsible of the metabolic disorders, and the elevated intake of fat induces lipid buildup, is a multifunctional scavenger receptor signaling those functions in high-affinity tissue uptake of long-chain fatty acids. In this study, we used series of molecular dynamics simulations of the wild type and mutants types K164A CD36 protein interacting with one palmitic acid (PLM) besides simulations of the wild type interacting with the three PLM to find out the mechanism of the functioning of the complex CD36/Fatty acids and the unraveling of the role of the mutation. Additionally we determined whether Lys164, mostly exposed to protein surface, played important roles in fatty acid uptake. These simulations revealed, the conformational changes induced by Lys164 residue and the altered interactions induced by the mutagenesis of surface lysine that was badly influencing the folding, utility, solubility, and stability form of the variant. Furthermore, Lys164 residue provided the structural basis of forming an opening at the region of principal portal for the dissociation of palmitic acid. The results of our simulations revealed hole two fatty acids found in CD36 cavity structure and it was the most preferred to CD36 structure stabilization.
Sergio A. Poveda-Cuevas, Fernando Luís Barroso da Silva, and Catherine Etchebest
American Chemical Society (ACS)
Viruses can impact and affect human populations in a severe way. The appropriate differentiation among several species or strains of viruses is one of the biggest challenges for virology and infectiology studies. The detection of measurables-quantified discrepancies allows for more accurate clinical diagnoses and treatments for viral diseases. In the present study, we have used a computational approach to explore the dynamical properties of the nonstructural protein 1 from two strains of Zika virus. Our results show that despite a high sequence similarity, the two viral proteins from different origins can exhibit significant dissimilar structural dynamics, which complement their reported differential virulence. The present study opens up new ways in the understanding of the infectivity for these biological entities.
Rajas Rao, Julien Diharce, Bérénice Dugué, Mariano A. Ostuni, Frédéric Cadet, and Catherine Etchebest
American Chemical Society (ACS)
Tarun Jairaj Narwani, Pierrick Craveur, Nicolas K. Shinada, Aline Floch, Hubert Santuz, Akhila Melarkode Vattekatte, Narayanaswamy Srinivasan, Joseph Rebehmed, Jean-Christophe Gelly, Catherine Etchebest,et al.
Informa UK Limited
Sergio A. Poveda-Cuevas, Catherine Etchebest, and Fernando L. Barroso da Silva
American Chemical Society (ACS)
Tatiana Galochkina, Matthieu Ng Fuk Chong, Lylia Challali, Sonia Abbar, and Catherine Etchebest
Springer Science and Business Media LLC
Tarun J. Narwani, Catherine Etchebest, Pierrick Craveur, Sylvain Léonard, Joseph Rebehmed, Narayanaswamy Srinivasan, Aurélie Bornot, Jean-Christophe Gelly, and Alexandre G. de Brevern
Elsevier BV
S. Téletchéa, H. Santuz, S. Léonard, and C. Etchebest
Public Library of Science (PLoS)
Wilfried Condemine, Thibaut Eguether, Nathalie Couroussé, Catherine Etchebest, Agnes Gardet, Germain Trugnan, and Serge Chwetzoff
American Society for Microbiology
ABSTRACTThe interactions between viruses and actin cytoskeleton have been widely studied. We showed that rotaviruses remodel microfilaments in intestinal cells and demonstrated that this was due to the VP4 spike protein. Microfilaments mainly occur in the apical domain of infected polarized enterocytes and favor the polarized apical exit of viral progeny. The present work aims at the identification of molecular determinants of actin-VP4 interactions. We used various deletion mutants of VP4 that were transfected into Cos-7 cells and analyzed interactions by immunofluorescence confocal microscopy. It has been established that the C-terminal part of VP4 is embedded within viral particles when rotavirus assembles. The use of specific monoclonal antibodies demonstrated that VP4 is expressed in different forms in infected cells: classically as spike on the outer layer of virus particles, but also as free soluble protein in the cytosol. The C terminus of free VP4 was identified as interacting with actin microfilaments. The VP4 actin binding domain is unable to promote microfilament remodeling by itself; the coiled-coil domain is also required in this process. This actin-binding domain was shown to dominate a previously identified peroxisomal targeting signal, located in the three last amino acids of VP4. The newly identified actin-binding domain is highly conserved in rotavirus strains from species A, B, and C, suggesting that actin binding and remodeling is a general strategy for rotavirus exit. This provides a novel mechanism of protein-protein interactions, not involving cell signaling pathways, to facilitate rotavirus exit.IMPORTANCERotaviruses are causal agents of acute infantile viral diarrhea. In intestinal cells,in vitroas well asin vivo, virus assembly and exit do not imply cell lysis but rely on an active process in which the cytoskeleton plays a major role. We describe here a novel molecular mechanism by which the rotavirus spike protein VP4 drives actin remodeling. This relies on the fact that VP4 occurs in different forms. Besides its structural function within the virion, a large proportion of VP4 is expressed as free protein. Here, we show that free VP4 possesses a functional actin-binding domain. This domain, in coordination with a coiled-coil domain, promotes actin cytoskeleton remodeling, thereby providing the capacity to destabilize the cell membrane and allow efficient rotavirus exit.
Sergio A. Poveda-Cuevas, Catherine Etchebest, and Fernando L. Barroso da Silva
American Chemical Society (ACS)
Tarun Narwani, Pierrick Craveur, Nicolas Shinada, Hubert Santuz, Joseph Rebehmed, Catherine Etchebest, and Brevern de
National Library of Serbia
Slim Azouzi, Hubert Santuz, Sandrine Morandat, Catia Pereira, Francine Côté, Olivier Hermine, Karim El Kirat, Yves Colin, Caroline Le Van Kim, Catherine Etchebest,et al.
Elsevier BV
Aurore Vaitinadapoule and Catherine Etchebest
Springer New York
Guillaume Postic, Yassine Ghouzam, Catherine Etchebest, and Jean-Christophe Gelly
Oxford University Press (OUP)