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Accueil > Départements > Biochimie, Biophysique et Biologie Structurale > Françoise OCHSENBEIN & Raphaël GUEROIS : Assemblage moléculaire et intégrité du génome

Publications de l’équipe


  • C. Caillet-Saguy, A. Toto, R. Guerois, P. Maisonneuve, E. di Silvio, K. Sawyer, S. Gianni, et N. Wolff, « Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains », Scientific Reports, vol. 7, nᵒ 1, p. 7875, 2017.
    Résumé : Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.
    Mots-clés : AMIG, B3S.

  • L. Celma, C. Corbinais, J. Vercruyssen, X. Veaute, I. L. de la Sierra-Gallay, R. Guérois, D. Busso, A. Mathieu, S. Marsin, S. Quevillon-Cheruel, et J. P. Radicella, « Structural basis for the substrate selectivity of Helicobacter pylori NucT nuclease activity », PLOS ONE, vol. 12, nᵒ 12, p. e0189049, déc. 2017.

  • Y. Duroc, R. Kumar, L. Ranjha, C. Adam, R. Guérois, K. Md Muntaz, M. - C. Marsolier-Kergoat, F. Dingli, R. Laureau, D. Loew, B. Llorente, J. - B. Charbonnier, P. Cejka, et V. Borde, « Concerted action of the MutLβ heterodimer and Mer3 helicase regulates the global extent of meiotic gene conversion », eLife, vol. 6, janv. 2017.
    Mots-clés : AMIG, B3S, biochemistry, Chromosomes, genes, INTGEN, Meiosis, mismatch repair, Recombination, S. cerevisiae.

  • A. Méneret, E. A. Franz, O. Trouillard, T. C. Oliver, Y. Zagar, S. P. Robertson, Q. Welniarz, R. J. M. K. Gardner, C. Gallea, M. Srour, C. Depienne, C. L. Jasoni, C. Dubacq, F. Riant, J. - C. Lamy, M. - P. Morel, R. Guérois, J. Andreani, C. Fouquet, M. Doulazmi, M. Vidailhet, G. A. Rouleau, A. Brice, A. Chédotal, I. Dusart, E. Roze, et D. Markie, « Mutations in the netrin-1 gene cause congenital mirror movements », The Journal of Clinical Investigation, 2017.
    Résumé : Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.
    Mots-clés : AMIG, B3S.

  • T. Q. Nguyen, M. Chenon, F. Vilela, C. Velours, M. Aumont-Nicaise, J. Andreani, P. F. Varela, P. Llinas, et J. Ménétrey, « Structural plasticity of the N-terminal capping helix of the TPR domain of kinesin light chain », PloS One, vol. 12, nᵒ 10, p. e0186354, 2017.
    Résumé : Kinesin1 plays a major role in neuronal transport by recruiting many different cargos through its kinesin light chain (KLC). Various structurally unrelated cargos interact with the conserved tetratricopeptide repeat (TPR) domain of KLC. The N-terminal capping helix of the TPR domain exhibits an atypical sequence and structural features that may contribute to the versatility of the TPR domain to bind different cargos. We determined crystal structures of the TPR domain of both KLC1 and KLC2 encompassing the N-terminal capping helix and show that this helix exhibits two distinct and defined orientations relative to the rest of the TPR domain. Such a difference in orientation gives rise, at the N-terminal part of the groove, to the formation of one hydrophobic pocket, as well as to electrostatic variations at the groove surface. We present a comprehensive structural analysis of available KLC1/2-TPR domain structures that highlights that ligand binding into the groove can be specific of one or the other N-terminal capping helix orientations. Further, structural analysis reveals that the N-terminal capping helix is always involved in crystal packing contacts, especially in a TPR1:TPR1' contact which highlights its propensity to be a protein-protein interaction site. Together, these results underline that the structural plasticity of the N-terminal capping helix might represent a structural determinant for TPR domain structural versatility in cargo binding.
    Mots-clés : AMIG, Amino Acid Motifs, Amino Acid Sequence, Animals, B3S, Conserved Sequence, Humans, Ligands, Mice, Microtubule-Associated Proteins, MIKICA, Models, Molecular, PF, PIM, Protein Conformation, alpha-Helical, Protein Domains.

  • P. V. Sauer, J. Timm, D. Liu, D. Sitbon, E. Boeri-Erba, C. Velours, N. Mücke, J. Langowski, F. Ochsenbein, G. Almouzni, et D. Panne, « Insights into the molecular architecture and histone H3-H4 deposition mechanism of yeast Chromatin assembly factor 1 », eLife, vol. 6, mars 2017.
    Mots-clés : AMIG, B3S, PF, PIM.

  • J. Yu, J. Andreani, F. Ochsenbein, et R. Guerois, « Lessons from (co-)evolution in the docking of proteins and peptides for CAPRI Rounds 28-35: Coevolution in CAPRI Rounds 28-35 », Proteins: Structure, Function, and Bioinformatics, vol. 85, nᵒ 3, p. 378-390, 2017.


  • M. Biondini, A. Sadou-Dubourgnoux, P. Paul-Gilloteaux, G. Zago, M. D. Arslanhan, F. Waharte, E. Formstecher, M. Hertzog, J. Yu, R. Guerois, A. Gautreau, G. Scita, J. Camonis, et M. C. Parrini, « Direct interaction between exocyst and Wave complexes promotes cell protrusions and motility », Journal of Cell Science, vol. 129, nᵒ 20, p. 3756-3769, 2016.
    Résumé : Coordination between membrane trafficking and actin polymerization is fundamental in cell migration, but a dynamic view of the underlying molecular mechanisms is still missing. The Rac1 GTPase controls actin polymerization at protrusions by interacting with its effector, the Wave regulatory complex (WRC). The exocyst complex, which functions in polarized exocytosis, has been involved in the regulation of cell motility. Here, we show a physical and functional connection between exocyst and WRC. Purified components of exocyst and WRC directly associate in vitro, and interactions interfaces are identified. The exocyst-WRC interaction is confirmed in cells by co-immunoprecipitation and is shown to occur independently of the Arp2/3 complex. Disruption of the exocyst-WRC interaction leads to impaired migration. By using time-lapse microscopy coupled to image correlation analysis, we visualized the trafficking of the WRC towards the front of the cell in nascent protrusions. The exocyst is necessary for WRC recruitment at the leading edge and for resulting cell edge movements. This direct link between the exocyst and WRC provides a new mechanistic insight into the spatio-temporal regulation of cell migration.
    Mots-clés : AMIG, B3S, Exocyst, Motility, Ral, Wave.

  • H. Delattre, O. Souiai, K. Fagoonee, R. Guerois, et M. - A. Petit, « Phagonaute: A web-based interface for phage synteny browsing and protein function prediction », Virology, vol. 496, p. 42-50, 2016.

  • M. F. Lensink, S. Velankar, A. Kryshtafovych, S. - Y. Huang, D. Schneidman-Duhovny, A. Sali, J. Segura, N. Fernandez-Fuentes, S. Viswanath, R. Elber, S. Grudinin, P. Popov, E. Neveu, H. Lee, M. Baek, S. Park, L. Heo, G. Rie Lee, C. Seok, S. Qin, H. - X. Zhou, D. W. Ritchie, B. Maigret, M. - D. Devignes, A. Ghoorah, M. Torchala, R. A. G. Chaleil, P. A. Bates, E. Ben-Zeev, M. Eisenstein, S. S. Negi, Z. Weng, T. Vreven, B. G. Pierce, T. M. Borrman, J. Yu, F. Ochsenbein, R. Guerois, A. Vangone, J. P. G. L. M. Rodrigues, G. van Zundert, M. Nellen, L. Xue, E. Karaca, A. S. J. Melquiond, K. Visscher, P. L. Kastritis, A. M. J. J. Bonvin, X. Xu, L. Qiu, C. Yan, J. Li, Z. Ma, J. Cheng, X. Zou, Y. Shen, L. X. Peterson, H. - R. Kim, A. Roy, X. Han, J. Esquivel-Rodriguez, D. Kihara, X. Yu, N. J. Bruce, J. C. Fuller, R. C. Wade, I. Anishchenko, P. J. Kundrotas, I. A. Vakser, K. Imai, K. Yamada, T. Oda, T. Nakamura, K. Tomii, C. Pallara, M. Romero-Durana, B. Jiménez-García, I. H. Moal, J. Férnandez-Recio, J. Y. Joung, J. Y. Kim, K. Joo, J. Lee, D. Kozakov, S. Vajda, S. Mottarella, D. R. Hall, D. Beglov, A. Mamonov, B. Xia, T. Bohnuud, C. A. Del Carpio, E. Ichiishi, N. Marze, D. Kuroda, S. S. Roy Burman, J. J. Gray, E. Chermak, L. Cavallo, R. Oliva, A. Tovchigrechko, et S. J. Wodak, « Prediction of homoprotein and heteroprotein complexes by protein docking and template-based modeling: A CASP-CAPRI experiment: Prediction of Homo and Heteroprotein Complexes by Protein Docking and Modeling », Proteins: Structure, Function, and Bioinformatics, vol. 84, p. 323-348, 2016.

  • P. Llinas, M. Chenon, T. Q. Nguyen, C. Moreira, A. de Régibus, A. Coquard, M. J. Ramos, R. Guérois, P. A. Fernandes, et J. Ménétrey, « Structure of a truncated form of leucine zipper II of JIP3 reveals an unexpected antiparallel coiled-coil arrangement », Acta Crystallographica Section F Structural Biology Communications, vol. 72, nᵒ 3, p. 198-206, mars 2016.

  • J. Yu et R. Guerois, « PPI4DOCK: large scale assessment of the use of homology models in free docking over more than 1000 realistic targets », Bioinformatics (Oxford, England), vol. 32, nᵒ 24, p. 3760-3767, 2016.
    Résumé : MOTIVATION: Protein-protein docking methods are of great importance for understanding interactomes at the structural level. It has become increasingly appealing to use not only experimental structures but also homology models of unbound subunits as input for docking simulations. So far we are missing a large scale assessment of the success of rigid-body free docking methods on homology models. RESULTS: We explored how we could benefit from comparative modelling of unbound subunits to expand docking benchmark datasets. Starting from a collection of 3157 non-redundant, high X-ray resolution heterodimers, we developed the PPI4DOCK benchmark containing 1417 docking targets based on unbound homology models. Rigid-body docking by Zdock showed that for 1208 cases (85.2%), at least one correct decoy was generated, emphasizing the efficiency of rigid-body docking in generating correct assemblies. Overall, the PPI4DOCK benchmark contains a large set of realistic cases and provides new ground for assessing docking and scoring methodologies. AVAILABILITY AND IMPLEMENTATION: Benchmark sets can be downloaded from CONTACT: guerois@cea.frSupplementary information: Supplementary data are available at Bioinformatics online.
    Mots-clés : AMIG, B3S.

  • J. Yu, M. Vavrusa, J. Andreani, J. Rey, P. Tufféry, et R. Guerois, « InterEvDock: a docking server to predict the structure of protein–protein interactions using evolutionary information », Nucleic Acids Research, vol. 44, nᵒ W1, p. W542-W549, juill. 2016.


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Publications majeures avant 2015

1. Richet N, Liu D, Legrand P, Velours C, Corpet A, Gaubert A, Bakail M, Moal-Raisin G, Guerois R, Compper C, Besle A, Guichard B, Almouzni G, Ochsenbein F (2015) Structural insight into how the human helicase subunit MCM2 may act as a histone chaperone together with ASF1 at the replication fork. Nucleic Acids Res. In press.

1. Lisboa J, Andreani J, Sanchez D, Boudes M, Collinet B, Liger D, van Tilbeurgh H, Guerois R*, Cheruel S* (2014) Molecular determinants of the DprA/RecA interaction for nucleation on ssDNA. Nucleic Acids Res 42(11):7395-408. (* co-last authors)

2. Pietrobon V, Fréon K, Hardy J, Costes A, Iraqui I, Ochsenbein F, Lambert SA (2014) The chromatin assembly factor 1 promotes Rad51-dependent template switches at replication forks by counteracting D-loop disassembly by the RecQ-type helicase Rqh1. PLoS Biol 12(10):e1001968.

3. Meurisse J, Bacquin A, Richet N, Charbonnier JB, Ochsenbein F, Peyroche A (2014) Hug1 is an intrinsically disordered protein that inhibits ribonucleotide reductase activity by directly binding Rnr2 subunit. Nucleic Acids Res. 42(21):13174-85.

4. Andreani J, Faure G, Guerois R (2013) InterEvScore : a novel coarse-grained interface scoring function using a multi-body statistical potential coupled to evolution. Bioinformatics 29 : 1742-1749.

5. Jiao Y*, Seeger K*, Lautrette A, Gaubert A, Mousson F, Guerois R, Mann C, Ochsenbein F (2012) Surprising complexity of the Asf1 histone chaperone-Rad53 kinase interaction. Proc Natl Acad Sci U S A 109 : 2866-2871

6. Barrault MB, Richet N, Godard C, Murciano B, Le Tallec B, Rousseau E, Legrand P, Charbonnier JB, Le Du MH, Guerois R, Ochsenbein F*, Peyroche A* (2012) Dual functions of the Hsm3 protein in chaperoning and scaffolding regulatory particle subunits during the proteasome assembly. Proc Natl Acad Sci U S A 109 : E1001-1010 (* co-last authors)

7. Faure G, Andreani J, Guerois R (2012) InterEvol database : exploring the structure and evolution of protein complex interfaces. Nucleic Acids Res 40 : D847-856

8. Lopes A, Amarir-Bouhram J, Faure G, Petit MA, Guerois R (2010) Detection of novel recombinases in bacteriophage genomes unveils Rad52, Rad51 and Gp2.5 remote homologs. Nucleic Acids Res 38 : 3952-3962

9. Madaoui H, Guerois R (2008) Coevolution at protein complex interfaces can be detected by the complementarity trace with important impact for predictive docking. Proc Natl Acad Sci U S A 105 : 7708-7713

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