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1. Structure of a human intramembrane ceramidase explains enzymatic dysfunction found in leukodystrophy

Author

Ieva Vasiliauskaité-Brooks, Robert D. Healey, Pascal Rochaix, Julie Saint-Paul, Rémy Sounier, Claire Grison, Thierry Waltrich-Augusto, Mathieu Fortier, François Hoh, Essa M. Saied, Christoph Arenz, Shibom Basu, Cédric Leyrat, Sébastien Granier, Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Ecologie Fonctionnelle et Evolutive (CEFE), Université Paul-Valéry - Montpellier 3 (UPVM)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre de Biochimie Structurale [Montpellier] (CBS), Institut für Chemie der Humboldt-Universität zu Berlin, Humboldt University Of Berlin, Laboratoire d'études spatiales et d'instrumentation en astrophysique (LESIA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Université Paul-Valéry - Montpellier 3 (UM3)-Institut National de la Recherche Agronomique (INRA)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-École pratique des hautes études (EPHE)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Humboldt Universität zu Berlin, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Observatoire de Paris, PSL Research University (PSL)-PSL Research University (PSL)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro)-Institut National de la Recherche Agronomique (INRA)-Université Paul-Valéry - Montpellier 3 (UPVM)-Institut national d’études supérieures agronomiques de Montpellier (Montpellier SupAgro), Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut de Recherche pour le Développement (IRD [France-Sud]), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Humboldt-Universität zu Berlin

Subjects
0301 basic medicine, Protein Conformation, Science, General Physics and Astronomy, Molecular Dynamics Simulation, Spodoptera, Crystallography, X-Ray, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Sf9 Cells, Animals, Humans, Point Mutation, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, Binding Sites, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], General Chemistry, 3. Good health, Molecular Docking Simulation, Hereditary Central Nervous System Demyelinating Diseases, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, HEK293 Cells, Alkaline Ceramidase, Calcium, lcsh:Q, Receptors, Adiponectin, 030217 neurology & neurosurgery
Abstract

Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. They are implicated in human pathophysiology, including progressive leukodystrophy, colon cancer as well as acute myeloid leukemia. We report here the crystal structure of the human ACER type 3 (ACER3). Together with computational studies, the structure reveals that ACER3 is an intramembrane enzyme with a seven transmembrane domain architecture and a catalytic Zn2+ binding site in its core, similar to adiponectin receptors. Interestingly, we uncover a Ca2+ binding site physically and functionally connected to the Zn2+ providing a structural explanation for the known regulatory role of Ca2+ on ACER3 enzymatic activity and for the loss of function in E33G-ACER3 mutant found in leukodystrophic patients., Alkaline ceramidases (ACERs) are a class of poorly understood transmembrane enzymes controlling the homeostasis of ceramides. Here authors solve the Xray structure of human ACER3 and uncover a Ca2+ binding site providing an explanation for the known regulatory role of Ca2+ on ACER3 activity.

Published
2018
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2. The RhoE/ROCK/ARHGAP25 signaling pathway controls cell invasion by inhibition of Rac activity

Author

Anne Blangy, Nabila Elarouci, Damien Planchon, Jessy Hasna, Franck Comunale, Stéphane Bodin, Mathieu Fortier, Aurélien de Reyniès, Cécile Gauthier-Rouvière, Sylvie Thuault, Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM), (le programme) Cartes d'identité des tumeurs (CIT), and Ligue Nationales Contre le Cancer (LNCC)

Subjects
0301 basic medicine, musculoskeletal diseases, rho GTP-Binding Proteins, Oncogene Proteins, Fusion, Cellular differentiation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Line, Extracellular matrix, 03 medical and health sciences, Cell Movement, hemic and lymphatic diseases, Rhabdomyosarcoma, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Muscle, Skeletal, Molecular Biology, Transcription factor, neoplasms, Rhabdomyosarcoma, Alveolar, ComputingMilieux_MISCELLANEOUS, Regulation of gene expression, rho-Associated Kinases, GTPase-Activating Proteins, Cell Differentiation, Forkhead Transcription Factors, Cell Biology, Articles, respiratory system, medicine.disease, female genital diseases and pregnancy complications, rac GTP-Binding Proteins, Gene Expression Regulation, Neoplastic, Cell Motility, 030104 developmental biology, Cell culture, Immunology, Alveolar rhabdomyosarcoma, Cancer research, Signal transduction, Signal Transduction
Abstract

New molecular pathways involved in alveolar rhabdomyosarcoma aggressiveness are found by identifying the RhoE/ROCK/ARHGAP25 signaling pathway as promoting the invasive potential of alveolar rhabdomyosarcoma., Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of skeletal muscle origin in children and adolescents. Among RMS subtypes, alveolar rhabdomyosarcoma (ARMS), which is characterized by the presence of the PAX3-FOXO1A or PAX7-FOXO1A chimeric oncogenic transcription factor, is associated with poor prognosis and a strong risk of metastasis compared with the embryonal subtype (ERMS). To identify molecular pathways involved in ARMS aggressiveness, we first characterized the migratory behavior of cell lines derived from ARMS and ERMS biopsies using a three-dimensional spheroid cell invasion assay. ARMS cells were more invasive than ERMS cells and adopted an ellipsoidal morphology to efficiently invade the extracellular matrix. Moreover, the invasive potential of ARMS cells depended on ROCK activity, which is regulated by the GTPase RhoE. Specifically, RhoE expression was low in ARMS biopsies, and its overexpression in ARMS cells reduced their invasion potential. Conversely, ARHGAP25, a GTPase-activating protein for Rac, was up-regulated in ARMS biopsies. Moreover, we found that ARHGAP25 inhibits Rac activity downstream of ROCKII and is required for ARMS cell invasion. Our results indicate that the RhoE/ROCK/ARHGAP25 signaling pathway promotes ARMS invasive potential and identify these proteins as potential therapeutic targets for ARMS treatment.

Published
2016
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