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7 results on '"A. Molza"'

1. Innovative interactive flexible docking method for multi-scale reconstruction elucidates dystrophin molecular assembly

Author

Mirjam Czjzek, Jean-François Hubert, E. Le Rumeur, Marc Baaden, Olivier Delalande, Nicolas Ferey, Alex Tek, Benoist Laurent, Anne-Elisabeth Molza, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Espaces acoustiques et cognitifs (EAC), Sciences et Technologies de la Musique et du Son (STMS), Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche et Coordination Acoustique/Musique (IRCAM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Végétaux marins et biomolécules, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-GOEMAR-Centre National de la Recherche Scientifique (CNRS), Structures et interactions moléculaires, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), The Association Française contre les Myopathies (AFM) and Rennes Métropole provided financial support, and Anne-Elisabeth Molza PhD fellow is funded by an AFM grant. Computer time was provided by GENCI (IDRIS and CINES, grant DYSIM 076816). M.B. thanks the French Agency for Research (Grant 'ExaViz', ANR-11-MONU-003) and the 'Initiative d'Excellence' program from the French State (Grant 'DYNAMO', ANR-11-LABX-0011) for support., ANR-11-LABX-0011,DYNAMO,Dynamique des membranes transductrices d'énergie : biogénèse et organisation supramoléculaire.(2011), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes 1 (UR1), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Espaces acoustiques et cognitifs, Laboratoire d'Informatique pour la Mécanique et les Sciences de l'Ingénieur (LIMSI), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE)-Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Université Paris Diderot - Paris 7 (UPD7)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), ExaViz, ANR-11-MONU-003, DYNAMO, ANR-11-LABX-0011,ExaViz, ANR-11-MONU-003, and DYNAMO, ANR-11-LABX-0011

Subjects
Models, Molecular, business.product_category, biology, business.industry, Computer science, X-Rays, Spring system, Nanotechnology, Grid, Elastic network, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Computational science, Dystrophin, Molecular Docking Simulation, Software, Docking (molecular), Laptop, biology.protein, Scattering, Radiation, Physical and Theoretical Chemistry, General-purpose computing on graphics processing units, business
Abstract

International audience; At present, our molecular knowledge of dystrophin, the protein encoded by the DMD gene and mutated in myopathy patients, remains limited. To get around the absence of its atomic structure, we have developed an innovative interactive docking method based on the BioSpring software in combination with Small-angle X-ray Scattering (SAXS) data. BioSpring allows interactive handling of biological macromolecules thanks to an augmented Elastic Network Model (aENM) that combines the spring network with non-bonded terms between atoms or pseudo-atoms. This approach can be used for building molecular assemblies even on a desktop or a laptop computer thanks to code optimizations including parallel computing and GPU programming. By combining atomistic and coarse-grained models, the approach significantly simplifies the set-up of multi-scale scenarios. BioSpring is remarkably efficient for the preparation of numeric simulations or for the design of biomolecular models integrating qualitative experimental data restraints. The combination of this program and SAXS allowed us to propose the first high-resolution models of the filamentous central domain of dystrophin, covering repeats 11 to 17. Low-resolution interactive docking experiments driven by a potential grid enabled us to propose how dystrophin may associate with F-actin and nNOS. This information provides an insight into medically relevant discoveries to come.

Published
2014
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2. Residues in the fingers domain of the translesion DNA polymerase DinB enable its unique participation in error-prone double-strand break repair

Author

Claudia Danilowicz, Veronica G. Godoy, Tommy F. Tashjian, Brian H. Nguyen, Mara Prentiss, Anne-Elizabeth Molza, Chantal Prévost, Northeastern University [Boston], Harvard University [Cambridge], Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Graduate Research and Dissertation Grant, Northeastern University College of Science.Initiative d'Excellence Program of the French State Grant DYNAMO, ANR-11- LABX-0011-01. National Institutes of Health NIGMS Grant RO1GM088230 (to V. G. G.) and Northeastern University.

Subjects
0301 basic medicine, DNA, Bacterial, DNA repair, DNA polymerase, DNA, Single-Stranded, homologous recombination, DNA and Chromosomes, Biochemistry, 03 medical and health sciences, Escherichia coli, DNA Breaks, Double-Stranded, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Polymerase, RecA, 030102 biochemistry & molecular biology, biology, DNA synthesis, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Escherichia coli Proteins, DNA replication, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Double Strand Break Repair, DinB, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, DNA-Binding Proteins, Rec A Recombinases, 030104 developmental biology, Coding strand, DNA polymerase IV, biology.protein, Biophysics, DNA damage, Homologous recombination
Abstract

International audience; The evolutionarily conserved Escherichia coli translesion DNA polymerase IV (DinB) is one of three enzymes that can bypass potentially deadly DNA lesions on the template strand during DNA replication. Remarkably, however, DinB is the only known translesion DNA polymerase active in RecA-mediated strand exchange during error-prone double-strand break repair. In this process, a single-stranded DNA (ssDNA)–RecA nucleoprotein filament invades homologous dsDNA, pairing the ssDNA with the complementary strand in the dsDNA. When exchange reaches the 3′ end of the ssDNA, a DNA polymerase can add nucleotides onto the end, using one strand of dsDNA as a template and displacing the other. It is unknown what makes DinB uniquely capable of participating in this reaction. To explore this topic, we performed molecular modeling of DinB's interactions with the RecA filament during strand exchange, identifying key contacts made with residues in the DinB fingers domain. These residues are highly conserved in DinB, but not in other translesion DNA polymerases. Using a novel FRET-based assay, we found that DinB variants with mutations in these conserved residues are less effective at stabilizing RecA-mediated strand exchange than native DinB. Furthermore, these variants are specifically deficient in strand displacement in the absence of RecA filament. We propose that the amino acid patch of highly conserved residues in DinB-like proteins provides a mechanistic explanation for DinB's function in strand exchange and improves our understanding of recombination by providing evidence that RecA plays a role in facilitating DinB's activity during strand exchange.

Published
2018
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3. Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Author

Olivier Delalande, Angélique Chéron, Céline Raguénès-Nicol, Mirjam Czjzek, Arnaud Bondon, Christophe Tascon, Jean-François Hubert, Nicolas Ferey, Elisabeth Le Rumeur, Emmanuel Giudice, Aurélie Nicolas, Émeline Pollet, Marc Baaden, Javier Pérez, Raphael Dos Santos Morais, Marine Guilbaud, Pierre Roblin, Anne-Elisabeth Molza, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), European Synchrotron Radiation Facility (ESRF), Laboratoire Léon Brillouin (LLB - UMR 12), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique pour la Mécanique et les Sciences de l'Ingénieur (LIMSI), Université Paris-Sud - Paris 11 (UP11)-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Laboratoire de Biologie Intégrative des Modèles Marins (LBI2M), Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Association Francaise Contre les Myopathies, AFM-Telethon, Conseil Regional de Bretagne, RTR Biologie-Sante of the Universite Europeenne de Bretagne, Grand Equipement National de Calcul Intensif-GENCI Program (DYSIM Project), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Delalande, Olivier, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Saclay-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Saclay (COmUE), Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Unité de Recherche sur les Biopolymères leurs Interactions et Assemblages (URBIA), Sorbonne Universités, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biochimie et Génétique Moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Paris Saclay (COmUE)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université - UFR d'Ingénierie (UFR 919), Sorbonne Université (SU)-Sorbonne Université (SU)-Université Paris-Saclay-Université Paris-Sud - Paris 11 (UP11), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent

Subjects
0301 basic medicine, Reading Frames, multiresolution modeling, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], small-angle X-ray scattering (SAXS), Small angle X-ray scattering, Nitric Oxide Synthase Type I, Biochemistry, Exon, 0302 clinical medicine, dystrophin central domain, X-Ray Diffraction, dystrophin, molecular docking, muscular dystrophy, nitric oxide synthase, Becker muscular dystrophy, Spectrin, Muscular dystrophy, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Bases of Disease, Exons, musculoskeletal system, Phenotype, Cell biology, Nitric oxide synthase, Molecular Docking Simulation, Solutions, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], medicine.symptom, Dystrophin, Muscle contraction, musculoskeletal diseases, congenital, hereditary, and neonatal diseases and abnormalities, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], 03 medical and health sciences, Protein Domains, Scattering, Small Angle, medicine, Humans, Molecular Biology, Binding Sites, neuronal Nitric Oxide Synthase, Cell Biology, medicine.disease, Muscular Dystrophy, Duchenne, 030104 developmental biology, multi resolution modeling, biology.protein, 030217 neurology & neurosurgery, Gene Deletion
Abstract

International audience; Dystrophin, encoded by the DMD gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the DMD gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin's central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45–47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD

Published
2018
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4. Human Dystrophin Structural Changes upon Binding to Anionic Membrane Lipids

Author

Mélanie Lagarrigue, Olivier Delalande, Thomas Chenuel, Raphael Dos Santos Morais, Sophie Combet, Elisabeth Le Rumeur, Jean-François Hubert, Anne-Elisabeth Molza, Dominique Mias-Lucquin, Angélique Chéron, Céline Raguénès-Nicol, Arnaud Bondon, Anne L. Martel, Marie-Sousai Appavou, Javier Pérez, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Laboratoire Léon Brillouin (LLB - UMR 12), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), SWING beamline, Biophysics Group (SWING), Synchrotron SOLEIL, Proteomics Core Facility (Protim), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Plateforme Génomique Santé Biogenouest®, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Laue-Langevin (ILL), ILL, Plate-forme Rennaise d'Imagerie et Spectroscopie Structurale et Métabolique (PRISM), Institut National de la Recherche Agronomique (INRA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Jülich Centre for Neutron Science (JCNS), Forschungszentrum Jülich GmbH, ARED #8893, Conseil Régional de Bretagne, 18211, AFM-Telethon, Laboratoire Léon Brillouin, thèses #2014, SOLEIL, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Beamline SWING, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Plateforme Génomique Santé Biogenouest®, Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes (UR)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)

Subjects
0301 basic medicine, Protein Conformation, alpha-Helical, Duchenne muscular dystrophy, Membrane lipids, [SDV]Life Sciences [q-bio], [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Biophysics, Model lipid bilayer, Gene mutation, Molecular Dynamics Simulation, 01 natural sciences, Dystrophin, 03 medical and health sciences, Membrane Lipids, Protein structure, 0103 physical sciences, medicine, Humans, [CHIM]Chemical Sciences, Integral membrane protein, Micelles, Sarcolemma, 010304 chemical physics, biology, Chemistry, Proteins, medicine.disease, 030104 developmental biology, biology.protein, Protein Binding
Abstract

International audience; Scaffolding proteins play important roles in supporting the plasma membrane (sarcolemma) of muscle cells. Among them, dystrophin strengthens the sarcolemma through protein-lipid interactions, and its absence due to gene mutations leads to the severe Duchenne muscular dystrophy. Most of the dystrophin protein consists of a central domain made of 24 spec-trin-like coiled-coil repeats (R). Using small angle neutron scattering (SANS) and the contrast variation technique, we specifically probed the structure of the three first consecutive repeats 1-3 (R1-3), a part of dystrophin known to physiologically interact with membrane lipids. R1-3 free in solution was compared to its structure adopted in the presence of phospholipid-based bicelles. SANS data for the protein/lipid complexes were obtained with contrast-matched bicelles under various phospholipid compositions to probe the role of electrostatic interactions. When bound to anionic bicelles, large modifications of the protein three-dimensional structure were detected, as revealed by a significant increase of the protein gyration radius from 42 5 1 to 60 5 4 Å. R1-3/anionic bicelle complexes were further analyzed by coarse-grained molecular dynamics simulations. From these studies, we report an all-atom model of R1-3 that highlights the opening of the R1 coiled-coil repeat when bound to the membrane lipids. This model is totally in agreement with SANS and click chemistry/mass spectrometry data. We conclude that the sarcolemma membrane anchoring that occurs during the contraction/elongation process of muscles could be ensured by this coiled-coil opening. Therefore, understanding these structural changes may help in the design of rationalized shortened dystrophins for gene therapy. Finally, our strategy opens up new possibilities for structure determination of peripheral and integral membrane proteins not compatible with different high-resolution structural methods.

Published
2018
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5. Molecular Clues about the Dystrophin–Neuronal Nitric Oxide Synthase Interaction: A Theoretical Approach

Author

Aurélie Nicolas, Anne-Elisabeth Molza, Elisabeth Le Rumeur, Olivier Delalande, Yoann Laurin, Emmanuel Giudice, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structures et interactions moléculaires, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1)

Subjects
musculoskeletal diseases, Amino Acid Motifs, MESH: Protein Structure, Secondary, MESH: Nitric Oxide Synthase Type I, Nitric Oxide Synthase Type I, Molecular Dynamics Simulation, Biology, Biochemistry, Protein Structure, Secondary, Dystrophin, MESH: Amino Acid Motifs, 03 medical and health sciences, 0302 clinical medicine, MESH: Dystrophin, In vivo, Utrophin, MESH: Protein Binding, Humans, Myocyte, MESH: Molecular Dynamics Simulation, Homology modeling, [SDV.BDD]Life Sciences [q-bio]/Development Biology, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, MESH: Humans, Protein superfamily, musculoskeletal system, In vitro, Cell biology, Cytosol, biology.protein, 030217 neurology & neurosurgery, Protein Binding
Abstract

International audience; Dystrophin is a large skeletal muscle protein located at the internal face of the plasma membrane and interacting with membrane phospholipids and a number of cytosolic proteins. Binding of neuronal nitric oxide synthase (nNOS) to dystrophin appears to be crucial for exercise-induced increases in blood supply in muscle cells. By contrast, utrophin, the developmental homologous protein of dystrophin, does not display nNOS interaction. Recent in vitro and in vivo experiments showed that the dystrophin region involved in nNOS binding is located in spectrin-like repeats R16 and R17 of its filamentous central domain. Using homology modeling and atomistic molecular dynamics simulation, we compared the structural organization and surface potentials of dystrophin, utrophin, and chimeric fragments, thus revisiting the dystrophin-nNOS binding region. Our simulation results are in good agreement with experimental data. They provide a three-dimensional representation of the repeats and give insight into the molecular organization of the regions involved in dystrophin-nNOS interaction. This study also further elucidates the physical properties crucial for this interaction, particularly the presence of a large hydrophobic patch. These results will be helpful to improving our understanding of the phenotypic features of patients bearing mutations in the nNOS-binding region of dystrophin.

Published
2013
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6. Structural Basis of Neuronal Nitric-Oxide Synthase Interaction with Dystrophin Repeats 16 and 17

Author

Nick Menhart, Olivier Delalande, Elisabeth Le Rumeur, Jean-François Hubert, Khushdeep Mangat, Anne-Elisabeth Molza, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Division of Biology, Illinois Institute of Technology (IIT), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )

Subjects
musculoskeletal diseases, muscular dystrophy, congenital, hereditary, and neonatal diseases and abnormalities, Protein Conformation, nitric-oxide synthase, Duchenne muscular dystrophy, [SDV]Life Sciences [q-bio], PDZ domain, Nitric Oxide Synthase Type I, Molecular Dynamics Simulation, Biology, Biochemistry, Protein Structure, Secondary, dystrophin, 03 medical and health sciences, 0302 clinical medicine, Dystrophin-associated protein complex, Utrophin, medicine, Humans, Scattering, Radiation, Biotinylation, Muscular dystrophy, Muscle, Skeletal, Molecular Biology, 030304 developmental biology, 0303 health sciences, Alanine, Binding Sites, X-Rays, Exons, Cell Biology, Alanine scanning, medicine.disease, musculoskeletal system, Dystrophin-associated protein, molecular dynamics, Protein Structure, Tertiary, Cell biology, Mutagenesis, Dystrophin-Associated Proteins, Mutation, biology.protein, site-directed mutagenesis, Dystrophin, Molecular Biophysics, 030217 neurology & neurosurgery, Protein Binding
Abstract

International audience; Duchenne muscular dystrophy is a lethal genetic defect that is associated with the absence of dystrophin protein. Lack of dystrophin protein completely abolishes muscular nitric oxide synthase (NOS) function as a regulator of blood flow during muscle contraction. In normal muscles, nNOS function is ensured by its localization at the sarcolemma through an interaction of its PDZ domain with dystrophin spectrin-like repeats R16 and R17. Early studies suggested that repeat R17 is the primary site of interaction but ignored the involved nNOS residues, and the R17 binding site has not been described at an atomic level. In this study, we characterized the specific amino acids involved in the binding site of nNOS-PDZ with dystrophin R16-17 using combined experimental biochemical and structural in silico approaches. First, 32 alanine-scan mutagenesis variants of dystrophin R16-17 indicated the regions where mutagenesis modified the affinity of the dystrophin interaction with the nNOS-PDZ. Second, using small angle X-ray scattering-based models of dystrophin R16-17 and molecular docking methods, we generated atomic models of the dystrophin R16-17: nNOS-PDZ complex that correlated well with the alanine-scanning-identified regions of dystrophin. The structural regions constituting the dystrophin interaction surface involve the A/B loop and the N-terminal end of helix B of repeat R16 and the N-terminal end of helix A' and a small fraction of helix B' and a large part of the helix C' of repeat R17. The interaction surface of nNOS-PDZ involves its main β-sheet and its specific C-terminal β-finger.

Published
2015
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7. Early expression of ΔCH1 dystrophin isoform reverses or prevents muscular dystrophy in the Dup2 mouse

Author

Felecia Gumienny, Nicolas Wein, James M. Ervasti, Nianyuan Huang, Tabatha R. Simmons, A. Molza, O. Delalande, Robert B. Weiss, Kevin M. Flanigan, and Adeline Vulin

Subjects
Gene isoform, Neurology, biology, Pediatrics, Perinatology and Child Health, Utrophin, medicine, biology.protein, Neurology (clinical), Muscular dystrophy, medicine.disease, Dystrophin, Genetics (clinical), Cell biology
Published
2015
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