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  • 1
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    The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-02-06
    Description: The influenza virus polymerase, a heterotrimer composed of three subunits, PA, PB1 and PB2, is responsible for replication and transcription of the eight separate segments of the viral RNA genome in the nuclei of infected cells. The polymerase synthesizes viral messenger RNAs using short capped primers derived from cellular transcripts by a unique 'cap-snatching' mechanism. The PB2 subunit binds the 5' cap of host pre-mRNAs, which are subsequently cleaved after 10-13 nucleotides by the viral endonuclease, hitherto thought to reside in the PB2 (ref. 5) or PB1 (ref. 2) subunits. Here we describe biochemical and structural studies showing that the amino-terminal 209 residues of the PA subunit contain the endonuclease active site. We show that this domain has intrinsic RNA and DNA endonuclease activity that is strongly activated by manganese ions, matching observations reported for the endonuclease activity of the intact trimeric polymerase. Furthermore, this activity is inhibited by 2,4-dioxo-4-phenylbutanoic acid, a known inhibitor of the influenza endonuclease. The crystal structure of the domain reveals a structural core closely resembling resolvases and type II restriction endonucleases. The active site comprises a histidine and a cluster of three acidic residues, conserved in all influenza viruses, which bind two manganese ions in a configuration similar to other two-metal-dependent endonucleases. Two active site residues have previously been shown to specifically eliminate the polymerase endonuclease activity when mutated. These results will facilitate the optimisation of endonuclease inhibitors as potential new anti-influenza drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dias, Alexandre -- Bouvier, Denis -- Crepin, Thibaut -- McCarthy, Andrew A -- Hart, Darren J -- Baudin, Florence -- Cusack, Stephen -- Ruigrok, Rob W H -- England -- Nature. 2009 Apr 16;458(7240):914-8. doi: 10.1038/nature07745. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unit of Virus Host-Cell Interactions, UJF-EMBL-CNRS, UMR 5233, 6 rue Jules Horowitz, BP181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194459" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Catalytic Domain ; Endonucleases/chemistry/*metabolism ; Enzyme Stability ; Histidine/metabolism ; Humans ; Influenza A Virus, H3N2 Subtype/*enzymology ; Influenza A Virus, H5N1 Subtype/enzymology ; Influenzavirus C/enzymology ; Manganese/metabolism/pharmacology ; Models, Molecular ; Molecular Sequence Data ; Protein Subunits/*chemistry/*metabolism ; RNA Caps/*metabolism ; RNA Replicase/*chemistry/*metabolism ; Viral Proteins/*chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Structural insight into cap-snatching and RNA synthesis by influenza polymerase (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-11-20
    Description: Influenza virus polymerase uses a capped primer, derived by 'cap-snatching' from host pre-messenger RNA, to transcribe its RNA genome into mRNA and a stuttering mechanism to generate the poly(A) tail. By contrast, genome replication is unprimed and generates exact full-length copies of the template. Here we use crystal structures of bat influenza A and human influenza B polymerases (FluA and FluB), bound to the viral RNA promoter, to give mechanistic insight into these distinct processes. In the FluA structure, a loop analogous to the priming loop of flavivirus polymerases suggests that influenza could initiate unprimed template replication by a similar mechanism. Comparing the FluA and FluB structures suggests that cap-snatching involves in situ rotation of the PB2 cap-binding domain to direct the capped primer first towards the endonuclease and then into the polymerase active site. The polymerase probably undergoes considerable conformational changes to convert the observed pre-initiation state into the active initiation and elongation states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reich, Stefan -- Guilligay, Delphine -- Pflug, Alexander -- Malet, Helene -- Berger, Imre -- Crepin, Thibaut -- Hart, Darren -- Lunardi, Thomas -- Nanao, Max -- Ruigrok, Rob W H -- Cusack, Stephen -- England -- Nature. 2014 Dec 18;516(7531):361-6. doi: 10.1038/nature14009. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] European Molecular Biology Laboratory, Grenoble Outstation, 71 Avenue des Martyrs, CS 90181, 38042 Grenoble Cedex 9, France [2] 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. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409151" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallization ; DNA-Directed RNA Polymerases/chemistry/*metabolism ; Gene Expression Regulation, Viral ; Influenza A virus/chemistry/*enzymology ; Influenza B virus/chemistry/*enzymology ; *Models, Molecular ; Promoter Regions, Genetic ; Protein Binding ; Protein Structure, Tertiary ; *RNA Caps/chemistry/metabolism ; RNA, Viral/*biosynthesis/*chemistry ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Crystal structure of the rabies virus nucleoprotein-RNA complex (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-06-17
    Description: Negative-strand RNA viruses condense their genome into a helical nucleoprotein-RNA complex, the nucleocapsid, which is packed into virions and serves as a template for the RNA-dependent RNA polymerase complex. The crystal structure of a recombinant rabies virus nucleoprotein-RNA complex, organized in an undecameric ring, has been determined at 3.5 angstrom resolution. Polymerization of the nucleoprotein is achieved by domain exchange between protomers, with flexible hinges allowing nucleocapsid formation. The two core domains of the nucleoprotein clamp around the RNA at their interface and shield it from the environment. RNA sequestering by nucleoproteins is likely a common mechanism used by negative-strand RNA viruses to protect their genomes from the innate immune response directed against viral RNA in human host cells at certain stages of an infectious cycle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Albertini, Aurelie A V -- Wernimont, Amy K -- Muziol, Tadeusz -- Ravelli, Raimond B G -- Clapier, Cedric R -- Schoehn, Guy -- Weissenhorn, Winfried -- Ruigrok, Rob W H -- New York, N.Y. -- Science. 2006 Jul 21;313(5785):360-3. Epub 2006 Jun 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Virologie Moleculaire et Structurale, FRE 2854 Universite Joseph Fourier-CNRS, Boite Postale 181, 38042 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16778023" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Crystallography, X-Ray ; DNA-Directed RNA Polymerases/metabolism ; Genome, Viral ; Models, Molecular ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleocapsid Proteins/*chemistry/metabolism ; Phosphoproteins/metabolism ; Phosphorylation ; Protein Conformation ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/chemistry ; RNA, Viral/*chemistry/genetics/metabolism ; Rabies virus/*chemistry/genetics ; Recombinant Proteins/chemistry ; Ribonucleoproteins/*chemistry
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Structural virology. Near-atomic cryo-EM structure of the helical measles virus nucleocapsid (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-04-18
    Description: Measles is a highly contagious human disease. We used cryo-electron microscopy and single particle-based helical image analysis to determine the structure of the helical nucleocapsid formed by the folded domain of the measles virus nucleoprotein encapsidating an RNA at a resolution of 4.3 angstroms. The resulting pseudoatomic model of the measles virus nucleocapsid offers important insights into the mechanism of the helical polymerization of nucleocapsids of negative-strand RNA viruses, in particular via the exchange subdomains of the nucleoprotein. The structure reveals the mode of the nucleoprotein-RNA interaction and explains why each nucleoprotein of measles virus binds six nucleotides, whereas the respiratory syncytial virus nucleoprotein binds seven. It provides a rational basis for further analysis of measles virus replication and transcription, and reveals potential targets for drug design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gutsche, Irina -- Desfosses, Ambroise -- Effantin, Gregory -- Ling, Wai Li -- Haupt, Melina -- Ruigrok, Rob W H -- Sachse, Carsten -- Schoehn, Guy -- New York, N.Y. -- Science. 2015 May 8;348(6235):704-7. doi: 10.1126/science.aaa5137. Epub 2015 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. gutsche@embl.fr. ; Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69917 Heidelberg, Germany. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. ; Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France. ; Institut Laue-Langevin, 38000 Grenoble, France. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883315" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; Humans ; Measles/*virology ; Measles virus/chemistry/*ultrastructure ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleocapsid/chemistry/*ultrastructure ; Nucleoproteins/chemistry/ultrastructure ; Protein Structure, Secondary ; RNA, Viral/chemistry/ultrastructure ; Viral Proteins/chemistry/ultrastructure
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Intrinsic disorder in measles virus nucleocapsids (2011)
    National Academy of Sciences
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    Publication Date: 2011-05-25
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Structure of the measles virus H glycoprotein sheds light on an efficient vaccine (2007)
    National Academy of Sciences
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    Publication Date: 2007-12-17
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    A structural model for unfolded proteins from residual dipolar couplings and small-angle x-ray scattering (2005)
    National Academy of Sciences
    Details
    Publication Date: 2005-11-11
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    Intrinsic disorder in measles virus nucleocapsids [Biophysics and Computational Biology] (2011)
    National Academy of Sciences
    Details
    Publication Date: 2011-06-15
    Description: The genome of measles virus is encapsidated by multiple copies of the nucleoprotein (N), forming helical nucleocapsids of molecular mass approaching 150 Megadalton. The intrinsically disordered C-terminal domain of N (NTAIL) is essential for transcription and replication of the virus via interaction with the phosphoprotein P of the viral polymerase complex. The molecular recognition element (MoRE) of NTAIL that binds P is situated 90 amino acids from the folded RNA-binding domain (NCORE) of N, raising questions about the functional role of this disordered chain. Here we report the first in situ structural characterization of NTAIL in the context of the entire N-RNA capsid. Using nuclear magnetic resonance spectroscopy, small angle scattering, and electron microscopy, we demonstrate that NTAIL is highly flexible in intact nucleocapsids and that the MoRE is in transient interaction with NCORE. We present a model in which the first 50 disordered amino acids of NTAIL are conformationally restricted as the chain escapes to the outside of the nucleocapsid via the interstitial space between successive NCORE helical turns. The model provides a structural framework for understanding the role of NTAIL in the initiation of viral transcription and replication, placing the flexible MoRE close to the viral RNA and, thus, positioning the polymerase complex in its functional environment.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Structural aspects of rabies virus replication (2007)
    Springer
    Details
    Publication Date: 2007-10-15
    Print ISSN: 1420-682X
    Electronic ISSN: 1420-9071
    Topics: Biology , Medicine
    Published by Springer
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  • 10
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    An ultraweak interaction in the intrinsically disordered replication machinery is essential for measles virus function (2018)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2018-08-23
    Description: Measles virus genome encapsidation is essential for viral replication and is controlled by the intrinsically disordered phosphoprotein (P) maintaining the nucleoprotein in a monomeric form (N) before nucleocapsid assembly. All paramyxoviruses harbor highly disordered amino-terminal domains (P NTD ) that are hundreds of amino acids in length and whose function remains unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we describe the structure and dynamics of the 90-kDa N 0 P NTD complex, comprising 450 disordered amino acids, at atomic resolution. NMR relaxation dispersion reveals the existence of an ultraweak N-interaction motif, hidden within the highly disordered P NTD , that allows P NTD to rapidly associate and dissociate from a specific site on N while tightly bound at the amino terminus, thereby hindering access to the surface of N. Mutation of this linear motif quenches the long-range dynamic coupling between the two interaction sites and completely abolishes viral transcription/replication in cell-based minigenome assays comprising integral viral replication machinery. This description transforms our understanding of intrinsic conformational disorder in paramyxoviral replication. The essential mechanism appears to be conserved across Paramyxoviridae, opening unique new perspectives for drug development against this family of pathogens.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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