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1. Targeting the conserved active site of splicing machines with specific and selective small molecule modulators

Author

Ilaria Silvestri, Jacopo Manigrasso, Alessandro Andreani, Nicoletta Brindani, Caroline Mas, Jean-Baptiste Reiser, Pietro Vidossich, Gianfranco Martino, Andrew A. McCarthy, Marco De Vivo, and Marco Marcia

Subjects
Science
Abstract

Abstract The self-splicing group II introns are bacterial and organellar ancestors of the nuclear spliceosome and retro-transposable elements of pharmacological and biotechnological importance. Integrating enzymatic, crystallographic, and simulation studies, we demonstrate how these introns recognize small molecules through their conserved active site. These RNA-binding small molecules selectively inhibit the two steps of splicing by adopting distinctive poses at different stages of catalysis, and by preventing crucial active site conformational changes that are essential for splicing progression. Our data exemplify the enormous power of RNA binders to mechanistically probe vital cellular pathways. Most importantly, by proving that the evolutionarily-conserved RNA core of splicing machines can recognize small molecules specifically, our work provides a solid basis for the rational design of splicing modulators not only against bacterial and organellar introns, but also against the human spliceosome, which is a validated drug target for the treatment of congenital diseases and cancers.

Published
2024
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2. Structural and biochemical characterisation of the Providencia stuartii arginine decarboxylase shows distinct polymerisation and regulation

Author

Matthew Jessop, Karine Huard, Ambroise Desfosses, Guillaume Tetreau, Diego Carriel, Maria Bacia-Verloop, Caroline Mas, Philippe Mas, Angélique Fraudeau, Jacques-Philippe Colletier, and Irina Gutsche

Subjects
Biology (General), QH301-705.5
Abstract

Jessop et. al. investigate the expression, activity, structure and supramolecular assembly of the arginine decarboxylase from Providencia stuartii, compare its polymers with those formed by the Escherichia coli lysine decarboxylase, and analyse the evolutionary conservation of the structural determinants of the polymerisation of these enzymes in enterobacteria.

Published
2022
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3. Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Author

Jan Felix, Claire Siebert, Julia Novion Ducassou, Jérôme Nigou, Pierre Simon Garcia, Angélique Fraudeau, Karine Huard, Caroline Mas, Céline Brochier-Armanet, Yohann Couté, Irina Gutsche, and Patricia Renesto

Subjects
Medicine, Science
Abstract

Abstract Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.

Published
2021
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4. Classification of the human phox homology (PX) domains based on their phosphoinositide binding specificities

Author

Mintu Chandra, Yanni K.-Y. Chin, Caroline Mas, J. Ryan Feathers, Blessy Paul, Sanchari Datta, Kai-En Chen, Xinying Jia, Zhe Yang, Suzanne J. Norwood, Biswaranjan Mohanty, Andrea Bugarcic, Rohan D. Teasdale, W. Mike Henne, Mehdi Mobli, and Brett M. Collins

Subjects
Science
Abstract

Phox homology (PX) domains are membrane interacting domains that bind to various lipids. Here authors screen all human PX domains systematically for their phospholipid preferences and define four classes and provide the basis for defining and predicting functional PX-membrane interactions.

Published
2019
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5. microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site

Author

Philipp Schult, Hanna Roth, Rebecca L. Adams, Caroline Mas, Lionel Imbert, Christian Orlik, Alessia Ruggieri, Anna M. Pyle, and Volker Lohmann

Subjects
Science
Abstract

The liver-specific microRNA-122 is an essential proviral host factor of Hepatitis C virus replication. Here the authors show that microRNA-122 functions as an RNA chaperone that guides the formation of a functional internal ribosome entry site by preventing energetically more favorable secondary structures within the HCV RNA genome.

Published
2018
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6. Structural and functional analysis of the Francisella lysine decarboxylase as a key actor in oxidative stress resistance

Author

Céline Brochier-Armanet, Yohann Couté, Pierre Simon Garcia, Angélique Fraudeau, Jan Felix, Patricia Renesto, Caroline Mas, Jérôme Nigou, Irina Gutsche, Karine Huard, Claire Siebert, Julia Novion Ducassou, Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Translational microbial Evolution and Engineering (TIMC-TrEE), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), Etude de la dynamique des protéomes (EDyP), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), The platforms of the Grenoble Instruct center (ISBG, UMS 3518 CNRS-CEA-UJF-EMBL), ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), ANR-10-INBS-0008,ProFI,Infrastructure Française de Protéomique(2010), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Brochier-Armanet, Céline, Infrastructure Française pour la Biologie Structurale Intégrée - - FRISBI2010 - ANR-10-INBS-0005 - INBS - VALID, Grenoble Alliance for Integrated Structural Cell Biology - - GRAL2010 - ANR-10-LABX-0049 - LABX - VALID, Infrastructure Française de Protéomique - - ProFI2010 - ANR-10-INBS-0008 - INBS - VALID, and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)

Subjects
Proteomics, 0301 basic medicine, DNA Repair, Carboxy-Lyases, Mutant, DETERMINANTS, SUSCEPTIBILITY, Virulence factor, Mice, Francisella tularensis, Tularemia, Cells, Cultured, Aromatic L-amino acid decarboxylase, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Multidisciplinary, Virulence, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Lysine decarboxylase, Biological techniques, TULAREMIA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Cell biology, Phylogenetics, ACID, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Francisella, Medicine, Microbiology techniques, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Science, 030106 microbiology, Proteomic analysis, Article, INTRACELLULAR SURVIVAL, 03 medical and health sciences, Bacterial Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Escherichia coli, Animals, VIBRIO-VULNIFICUS, BIOSYNTHESIS, Amino Acid Sequence, Structure determination, Gene, Mass spectrometry, Macrophages, TULARENSIS PATHOGENICITY ISLAND, Biology and Life Sciences, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, POLYAMINES, Oxidative Stress, 030104 developmental biology, VIRULENCE, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Sequence Alignment
Abstract

Francisella tularensis is one of the most virulent pathogenic bacteria causing the acute human respiratory disease tularemia. While the mechanisms underlying F. tularensis pathogenesis are largely unknown, previous studies have shown that a F. novicida transposon mutant with insertions in a gene coding for a putative lysine decarboxylase was attenuated in mouse spleen, suggesting a possible role of its protein product as a virulence factor. Therefore, we set out to structurally and functionally characterize the F. novicida lysine decarboxylase, which we termed LdcF. Here, we investigate the genetic environment of ldcF as well as its evolutionary relationships with other basic AAT-fold amino acid decarboxylase superfamily members, known as key actors in bacterial adaptative stress response and polyamine biosynthesis. We determine the crystal structure of LdcF and compare it with the most thoroughly studied lysine decarboxylase, E. coli LdcI. We analyze the influence of ldcF deletion on bacterial growth under different stress conditions in dedicated growth media, as well as in infected macrophages, and demonstrate its involvement in oxidative stress resistance. Finally, our mass spectrometry-based quantitative proteomic analysis enables identification of 80 proteins with expression levels significantly affected by ldcF deletion, including several DNA repair proteins potentially involved in the diminished capacity of the F. novicida mutant to deal with oxidative stress. Taken together, we uncover an important role of LdcF in F. novicida survival in host cells through participation in oxidative stress response, thereby singling out this previously uncharacterized protein as a potential drug target.

Published
2021

7. microRNA-122 amplifies hepatitis C virus translation by shaping the structure of the internal ribosomal entry site

Author

Christian Orlik, Anna Marie Pyle, Caroline Mas, Hanna Roth, Lionel Imbert, Rebecca L. Adams, Philipp Schult, Volker Lohmann, Alessia Ruggieri, Department of Infectious Diseases, University of Heidelberg, Medical Faculty, Department of Molecular, Cellular and Developmental Biology, Yale University [New Haven], Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Howard Hughes Medical Institute (HHMI), Universität Heidelberg [Heidelberg] = Heidelberg University, ANR-10-INBS-0005,FRISBI,Infrastructure Française pour la Biologie Structurale Intégrée(2010), ANR-10-LABX-0049,GRAL,Grenoble Alliance for Integrated Structural Cell Biology(2010), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), and Universität Heidelberg [Heidelberg]

Subjects
0301 basic medicine, Science, Genetic Vectors, General Physics and Astronomy, Hepacivirus, Biology, Internal Ribosome Entry Sites, Ribosome, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Genes, Reporter, Transduction, Genetic, Cell Line, Tumor, microRNA, Protein biosynthesis, Humans, Luciferases, lcsh:Science, Multidisciplinary, Oligoribonucleotides, 030102 biochemistry & molecular biology, Base Sequence, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Lentivirus, RNA, Translation (biology), General Chemistry, Ribosomal RNA, 3. Good health, Cell biology, Internal ribosome entry site, MicroRNAs, 030104 developmental biology, Viral replication, Gene Expression Regulation, Protein Biosynthesis, Host-Pathogen Interactions, Hepatocytes, Nucleic Acid Conformation, RNA, Viral, lcsh:Q, Ribosomes, Signal Transduction
Abstract

The liver-specific microRNA-122 (miR-122) recognizes two conserved sites at the 5′ end of the hepatitis C virus (HCV) genome and contributes to stability, translation, and replication of the viral RNA. We show that stimulation of the HCV internal ribosome entry site (IRES) by miR-122 is essential for efficient viral replication. The mechanism relies on a dual function of the 5′ terminal sequence in the complementary positive (translation) and negative strand (replication), requiring different secondary structures. Predictions and experimental evidence argue for several alternative folds involving the miR-binding region (MBR) adjacent to the IRES and interfering with its function. Mutations in the MBR, designed to suppress these dysfunctional structures indeed stimulate translation independently of miR-122. Conversely, MBR mutants favoring alternative folds show impaired IRES activity. Our results therefore suggest that miR-122 binding assists the folding of a functional IRES in an RNA chaperone-like manner by suppressing energetically favorable alternative secondary structures., The liver-specific microRNA-122 is an essential proviral host factor of Hepatitis C virus replication. Here the authors show that microRNA-122 functions as an RNA chaperone that guides the formation of a functional internal ribosome entry site by preventing energetically more favorable secondary structures within the HCV RNA genome.

Published
2018

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