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1. Exploring molecular determinants of polysaccharide lyase family 6–1 enzyme activity

Author

Sébastien Violot, Vinesh Jugnarain, Loic Carrique, William Helbert, Nushin Aghajari, Lionel Ballut, Xavier Robert, Aurélien Thureau, Frédéric Galisson, Léa Conchou, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut de Chimie du CNRS (INC)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches sur les Macromolécules Végétales (CERMAV ), and Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])

Subjects
Models, Molecular, CAZy, Subfamily, [SDV]Life Sciences [q-bio], 010402 general chemistry, Crystallography, X-Ray, 01 natural sciences, Biochemistry, Substrate Specificity, protein-carbohydrates recognition, 03 medical and health sciences, Carbohydrate Conformation, Humans, Amino Acid Sequence, Binding site, Mode of action, 030304 developmental biology, Polysaccharide-Lyases, chemistry.chemical_classification, 0303 health sciences, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], structure of alginate lyases, Substrate (chemistry), Enzyme assay, 0104 chemical sciences, Enzyme, chemistry, surface-binding site, Docking (molecular), biology.protein
Abstract

The polysaccharide lyase family 6 (PL6) represents one of the 41 polysaccharide lyase families classified in the CAZy database with the vast majority of its members being alginate lyases grouped into three subfamilies, PL6_1–3. To decipher the mode of recognition and action of the enzymes belonging to subfamily PL6_1, we solved the crystal structures of Pedsa0632, Patl3640, Pedsa3628 and Pedsa3807, which all show different substrate specificities and mode of action (endo-/exolyase). Thorough exploration of the structures of Pedsa0632 and Patl3640 in complex with their substrates as well as docking experiments confirms that the conserved residues in subsites −1 to +3 of the catalytic site form a common platform that can accommodate various types of alginate in a very similar manner but with a series of original adaptations bringing them their specificities of action. From comparative studies with existing structures of PL6_1 alginate lyases, we observe that in the right-handed parallel β-helix fold shared by all these enzymes, the substrate-binding site harbors the same overall conserved structures and organization. Despite this apparent similarity, it appears that members of the PL6_1 subfamily specifically accommodate and catalyze the degradation of different alginates suggesting that this common platform is actually a highly adaptable and specific tool.

Published
2021

2. Revisiting the molecular interactions between the tumor protein TCTP and the drugs sertraline/thioridazine

Author

Aurélien Thureau, Samir Messaoudi, Christina Sizun, Stephane Betzi, Florian Malard, Jérôme Dejeu, Amélie Chabrier, Naïma Nhiri, Eric Jacquet, Xu Zhang, Ewen Lescop, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Département de Chimie Moléculaire - Ingéniérie et Intéractions BioMoléculaires (DCM - I2BM), Département de Chimie Moléculaire (DCM), Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Beamline SWING, Synchrotron SOLEIL, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'ingénierie des systèmes macromoléculaires (LISM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), ED 515 - Complexité du vivant, Sorbonne Université (SU), Institut de Microbiologie de la Méditerranée (IMM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Drug, media_common.quotation_subject, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Thioridazine, Pharmacology, Ligands, Biochemistry, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Sertraline, Drug Discovery, medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, Mode of action, 030304 developmental biology, media_common, 0303 health sciences, Dose-Response Relationship, Drug, Molecular Structure, Chemistry, Kinase, Organic Chemistry, Tumor Protein, Translationally-Controlled 1, In vitro, 3. Good health, Protein destabilization, 030220 oncology & carcinogenesis, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Molecular Medicine, Phosphorylation, medicine.drug
Abstract

International audience; TCTP protein is a pharmacological target in cancer and TCTP inhibitors such as sertraline have been evaluated in clinical trials. The direct interaction of TCTP with the drugs sertraline and thioridazine has been reported in vitro by SPR experiments to be in the ~30-50 µM Kd range (Amson et al. Nature Med 2012), supporting a TCTP-dependent mode of action of the drugs on tumor cells. However, the molecular details of the interaction remain elusive although they are crucial to improve the efforts of on-going medicinal chemistry. In addition, TCTP can be phosphorylated by the Plk-1 kinase, which is indicative of poor prognosis in several cancers. The impact of phosphorylation on TCTP structure/dynamics and binding with therapeutical ligands remains unexplored. Here, we combined NMR, TSA, SPR, BLI and ITC techniques to probe the molecular interactions between TCTP with the drugs sertraline and thioridazine. We reveal that drug binding is much weaker than reported with an apparent ~mM Kd and leads to protein destabilization that obscured the analysis of the published SPR data. We further demonstrate by NMR and SAXS that TCTP S46 phosphorylation does not promote tighter interaction between TCTP and sertraline. Accordingly, we question the supported model in which sertraline and thioridazine directly interact with isolated TCTP in tumor cells and discuss alternative modes of action for the drugs in light of current literature.

Published
2021

3. Structural characterization of the RH1-LZI tandem of JIP3/4 highlights RH1 domains as a cytoskeletal motor-binding motif

Author

Julie Ménétrey, Aurélien Thureau, Christophe Velours, Magali Aumont-Nicaise, Fernando Vilela, Valérie Campanacci, Paola Llinas, Olena Pylypenko, Mélanie Chenon, Jessica Andreani, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biochimie Structurale des Microtubules, des Kinésines et de leurs Cargos (MIKICA), Département Biochimie, Biophysique et Biologie Structurale (B3S), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Mesures d'interactions protéine-protéine (PIM), Département Plateforme (PF I2BC), Laboratoire de Chimie Physique Macromoléculaire (LCPM), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL), Motilité structurale, Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Assemblage moléculaire et intégrité du génome (AMIG), Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Leucine zipper, Protein family, Bioinformatics, [SDV]Life Sciences [q-bio], Protein domain, Dynein, Myosin Type V, lcsh:Medicine, Nerve Tissue Proteins, GTPase, Article, 03 medical and health sciences, 0302 clinical medicine, Protein Domains, Humans, lcsh:Science, Cytoskeleton, ComputingMilieux_MISCELLANEOUS, Adaptor Proteins, Signal Transducing, Coiled coil, Leucine Zippers, Multidisciplinary, Myosin Heavy Chains, Chemistry, lcsh:R, Signal transducing adaptor protein, SAXS, Cell biology, Cytoskeletal proteins, 030104 developmental biology, lcsh:Q, Rab, 030217 neurology & neurosurgery
Abstract

JIP3 and JIP4 (JNK-interacting proteins 3 and 4) are adaptors for cargo recruitment by dynein/dynactin and kinesin1 motors. Both are dimers that are stabilised by two sections of leucine zipper coiled coils. The N-terminal Leucine Zipper I (LZI) belongs to a section that binds dynein-DLIC and kinesin1-KHC, whilst the medial Leucine Zipper II (LZII) binds dynactin-p150glued and kinesin1-KLC. Structural data is available for the LZII, but the LZI section is still uncharacterized. Here we characterize the N-terminal part of JIP3/4 which consists of an RH1 (RILP homology 1) domain followed by the LZI coiled coil using bioinformatical, biophysical and structural approaches. The RH1-LZI tandem of JIP3 associates as a high affinity homodimer exhibiting elongated alpha-helical fold. 3D homology modelling of the RH1-LZI tandem reveals that the kinesin1-KHC binding site mainly overlaps with the RH1 domain. A sequence comparison search indicates that only one other protein family has RH1 domains similar to those of JIP3/4, the RILP (Rab-interacting lysosomal protein) family which consists of adaptor proteins linking Rab GTPases to cytoskeletal motors. RILPL2 is recruited through its RH1 domain by the myosin 5a motor. Here, we showed that the RH1 domain of JIP3 also interacts with myosin 5 A in vitro, highlighting JIP3/4 as possible myosin 5a adaptors. Finally, we propose that JIP3/4 and RILP family members define a unique RH1/RH2-architecture adaptor superfamily linking cytoskeletal motors and Rab GTPases.

Published
2019

4. A Brief Survey of State-of-the-Art BioSAXS

Author

Pierre Roblina, Patrice Vachette, Javier Pérez, Aurélien Thureau, Thomas Bizien, Dominique Durand, Communication, information, médias (Paris), Unité Mixte de Recherches sur les Herbivores ( UMR 1213 Herbivores ), VetAgro Sup ( VAS ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique ( INRA ), SAD Paysage ( SAD Paysage ), Institut National de la Recherche Agronomique ( INRA ) -AGROCAMPUS OUEST, Institut de Biologie Intégrative de la Cellule ( I2BC ), Université Paris-Sud - Paris 11 ( UP11 ) -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, Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA), SWING beamline, Biophysics Group (SWING), Unité Mixte de Recherches sur les Herbivores - UMR 1213 (UMRH), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA), SAD Paysage (SAD Paysage), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, and Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay

Subjects
Models, Molecular, 0301 basic medicine, Beamline, conformation, Macromolecular Substances, [SDV]Life Sciences [q-bio], Nanotechnology, Biology, Biochemistry, Field (computer science), 03 medical and health sciences, X-Ray Diffraction, Structural Biology, Scattering, Small Angle, Instrumentation (computer programming), structure, solution, Structure (mathematical logic), Molecular Structure, [ SDV ] Life Sciences [q-bio], small-angle X-ray Scattering, Macromolecular crystallography, Computational Biology, General Medicine, Data science, Optical quality, hybrid methods, 030104 developmental biology, biological macromolecules, State (computer science), Software, Synchrotrons
Abstract

International audience; In the field of structural biology, Small Angle X-ray Scattering (SAXS) has undergone a tremendous evolution in the last two decades. From a craft reserved to a few experts in the late 80's, it has now turned into a high-throughput technique, following the same trend as macromolecular crystallography. Synchrotron radiation has played a key role in this evolution, by providing intense X-ray beams of high optical quality that made possible the recording of statistically meaningful data from weakly scattering biological solutions in a reasonable time. This, in turn, prompted the development of powerful and specific software for data analysis and modeling. In this mini-review, mainly addressed towards a broad readership, representing as many potential users, we try to summarize the latest aspects of evolution of BioSAXS, both conceptually and from the point of view of instrumentation. We emphasize the need for complementary experimental or computational techniques used in combination with SAXS. The great potential of these multi-pronged approaches is illustrated by a series of very recent studies covering the various ways and means of using BioSAXS.

Published
2016

5. SAXS and X-ray crystallography suggest an unfolding model for the GDP/GTP conformational switch of the small GTPase Arf6

Author

Mahel Zeghouf, Valérie Biou, Kaheina Aizel, Carine van Heijenoort, Eric Jacquet, Javier Pérez, Sebastian Hansson, Pierre Roblin, Eric Guittet, Aurélien Thureau, Jacqueline Cherfils, Bernard Guibert, Institut de Chimie des Substances Naturelles (ICSN), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)

Subjects
Protein Folding, Protein Conformation, Protein Data Bank (RCSB PDB), GTPase, Crystallography, X-Ray, Guanosine Diphosphate, 03 medical and health sciences, chemistry.chemical_compound, Protein structure, X-Ray Diffraction, Structural Biology, Scattering, Small Angle, Humans, Small GTPase, Molecular Biology, 030304 developmental biology, 0303 health sciences, ADP-Ribosylation Factors, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 030302 biochemistry & molecular biology, Crystallography, chemistry, ADP-Ribosylation Factor 6, Guanosine diphosphate, Thermodynamics, Protein folding, Guanosine Triphosphate, Guanine nucleotide exchange factor, Heteronuclear single quantum coherence spectroscopy
Abstract

International audience; The small GTPases Arf1 and Arf6 have nonoverlapping functions in cellular traffic despite their very high sequence and structural resemblance. Notably, the exquisite isoform specificity of their guanine nucleotide exchange factors and their distinctive sensitivity to the drug brefeldin A cannot be explained by any straightforward structural model. Here we integrated structural and spectroscopic methods to address this issue using Δ13Arf6-GDP, a truncated mutant that mimics membrane-bound Arf6-GDP. The crystal structure of Δ13Arf6-GDP reveals an unprecedented unfolding of the GTPase core β-strands, which is fully accounted for by small-angle X-ray scattering data in solution and by ab initio three-dimensional envelope calculation. NMR chemical shifts identify this structural disorder in Δ13Arf6-GDP, but not in the closely related Δ17Arf1-GDP, which is consistent with their comparative thermodynamic and hydrodynamic analyses. Taken together, these experiments suggest an unfolding model for the nucleotide switch of Arf6 and shed new light on its biochemical differences with Arf1.

Published
2010

6. Solution Structure of a Natural CPPC Active Site Variant, the Reduced Form of Thioredoxin h1 from Poplar

Author

Manh-Thong Cung, Eric Gelhaye, Nicolas Coudevylle, Jean-Pierre Jacquot, Aurélien Thureau, Christine Hemmerlin, Laboratoire de Chimie Physique Macromoléculaire (LCPM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Interactions Arbres-Microorganismes (IAM), and Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL)

Subjects
0106 biological sciences, Thioredoxin h, Molecular Sequence Data, Dihedral angle, Thioredoxin fold, Crystallography, X-Ray, 01 natural sciences, Biochemistry, CHEMICAL SHIFT ASSIGNMENT, Protein Structure, Secondary, 03 medical and health sciences, Amino Acids, Aromatic, Protein structure, Thioredoxins, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, Plant Proteins, 0303 health sciences, Carbon Isotopes, Binding Sites, SPECTROSCOPY, biology, Nitrogen Isotopes, Hydrogen bond, Chemistry, Active site, Hydrogen Bonding, POPLAR, NMR, RMN, Solutions, Crystallography, Populus, Heteronuclear molecule, THIOREDOXIN, biology.protein, PEUPLIER, Thermodynamics, Thioredoxin, Protons, Oxidation-Reduction, 010606 plant biology & botany
Abstract

International audience; Assignment of heteronuclear and homonuclear multidimensional NMR spectra permits determination of the first three-dimensional solution structure of a higher-plant thioredoxin h. The collection of 1906 distance restraints, 137 TALOS-derived dihedral restraints, and 66 hydrogen bonds was used in the restrained molecular dynamics protocol to calculate the structure of the reduced form of thioredoxin h1 from poplar with an atomic rmsd of 0.60 ± 0.12 Å. This enzyme exhibits an unusual active site with the sequence WCPPC and original properties in terms of stability and specificity. Compared to other known thioredoxin structures, thioredoxin h1 from poplar adopts the classical "Trx fold". Its atypical active site possesses a conformation similar to that of other common thioredoxins but appears to be more rigid. Moreover, the hydrogen bond network, stabilizing the in-core -sheet, is tighter than in Chlamydomonas reinhardtii, explaining the difference in thermostability.

Published
2005

7. Letter to the Editor: 1H, 13C and 15N resonance assignment of the reduced form of thioredoxin h1 from Poplar, a CPPC active site variant

Author

Nicolas Coudevylle, Christine Hemmerlin, Aurélien Thureau, Eric Gelhaye, Jean-Pierre Jacquot, Manh-Thong Cung, Laboratoire de Chimie Physique Macromoléculaire (LCPM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Interactions Arbres-Microorganismes (IAM), and Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL)

Subjects
0303 health sciences, RESONANCE ASSIGNMENT, biology, Chemistry, 030303 biophysics, Active site, Resonance, RESONANCE, Biochemistry, 3. Good health, 03 medical and health sciences, THIOREDOXINE, Nuclear magnetic resonance, DISULFIDE OXIDOREDUCTASE, THIOREDOXIN, biology.protein, Thioredoxin, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], DISULPHIDE OXYDOREDUCTASE, Spectroscopy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2004

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