title: Structural Analysis of dsRNA Binding to Anti-viral Pattern Recognition Receptors LGP2 and MDA5.
abstract: RIG-I and MDA5 sense virus-derived short 5'ppp blunt-ended or long dsRNA, respectively, causing interferon production. Non-signaling LGP2 appears to positively and negatively regulate MDA5 and RIG-I signaling, respectively. Co-crystal structures of chicken (ch) LGP2 with dsRNA display a fully or semi-closed conformation depending on the presence or absence of nucleotide. LGP2 caps blunt, 3' or 5' overhang dsRNA ends with 1 bp longer overall footprint than RIG-I. Structures of 1:1 and 2:1 complexes of chMDA5 with short dsRNA reveal head-to-head packing rather than the polar head-to-tail orientation described for long filaments. chLGP2 and chMDA5 make filaments with a similar axial repeat, although less co-operatively for chLGP2. Overall, LGP2 resembles a chimera combining a MDA5-like helicase domain and RIG-I like CTD supporting both stem and end binding. Functionally, RNA binding is required for LGP2-mediated enhancement of MDA5 activation. We propose that LGP2 end-binding may promote nucleation of MDA5 oligomerization on dsRNA.
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France; University Grenoble Alpes, Centre National de la Recherche Scientifique, EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France.
authors.forename: Emiko
authors.initials: E
authors.lastname: Uchikawa
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France; University Grenoble Alpes, Centre National de la Recherche Scientifique, EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Lethier
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France; University Grenoble Alpes, Centre National de la Recherche Scientifique, EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Malet
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, 69007 Lyon, France; Inserm, U1111, 69007 Lyon, France; CNRS, UMR5308, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, 69007 Lyon, France.
authors.forename: Joanna
authors.initials: J
authors.lastname: Brunel
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, 69007 Lyon, France; Inserm, U1111, 69007 Lyon, France; CNRS, UMR5308, 69007 Lyon, France; Ecole Normale Supérieure de Lyon, 69007 Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, 69007 Lyon, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Gerlier
authors.affiliation: European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France; University Grenoble Alpes, Centre National de la Recherche Scientifique, EMBL Unit of Virus Host-Cell Interactions, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France. Electronic address: cusack@embl.fr.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cusack
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D030161:Avian Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D002645:Chickens; D000071457:DEAD Box Protein 58 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D000072640:Interferon-Induced Helicase, IFIH1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012330:RNA, Double-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051192:Receptors, Pattern Recognition / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D030161:Avian Proteins; D012330:RNA, Double-Stranded; D016601:RNA-Binding Proteins; D051192:Receptors, Pattern Recognition; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D000071457:DEAD Box Protein 58; D000072640:Interferon-Induced Helicase, IFIH1