A Three-Stemmed mRNA Pseudoknot in the SARS Coronavirus Frameshift Signal
Identifieur interne : 001322 ( Pmc/Curation ); précédent : 001321; suivant : 001323A Three-Stemmed mRNA Pseudoknot in the SARS Coronavirus Frameshift Signal
Auteurs : Ewan P. Plant ; Gabriela C. Pérez-Alvarado ; Jonathan L. Jacobs ; Bani Mukhopadhyay ; Mirko Hennig ; Jonathan D. DinmanSource :
- PLoS Biology [ 1544-9173 ] ; 2005.
Abstract
A wide range of RNA viruses use programmed −1 ribosomal frameshifting for the production of viral fusion proteins. Inspection of the overlap regions between ORF1a and ORF1b of the SARS-CoV genome revealed that, similar to all coronaviruses, a programmed −1 ribosomal frameshift could be used by the virus to produce a fusion protein. Computational analyses of the frameshift signal predicted the presence of an mRNA pseudoknot containing three double-stranded RNA stem structures rather than two. Phylogenetic analyses showed the conservation of potential three-stemmed pseudoknots in the frameshift signals of all other coronaviruses in the GenBank database. Though the presence of the three-stemmed structure is supported by nuclease mapping and two-dimensional nuclear magnetic resonance studies, our findings suggest that interactions between the stem structures may result in local distortions in the A-form RNA. These distortions are particularly evident in the vicinity of predicted A-bulges in stems 2 and 3. In vitro and in vivo frameshifting assays showed that the SARS-CoV frameshift signal is functionally similar to other viral frameshift signals: it promotes efficient frameshifting in all of the standard assay systems, and it is sensitive to a drug and a genetic mutation that are known to affect frameshifting efficiency of a yeast virus. Mutagenesis studies reveal that both the specific sequences and structures of stems 2 and 3 are important for efficient frameshifting. We have identified a new RNA structural motif that is capable of promoting efficient programmed ribosomal frameshifting. The high degree of conservation of three-stemmed mRNA pseudoknot structures among the coronaviruses suggests that this presents a novel target for antiviral therapeutics.
Url:
DOI: 10.1371/journal.pbio.0030172
PubMed: 15884978
PubMed Central: 1110908
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A Three-Stemmed mRNA Pseudoknot in the SARS Coronavirus Frameshift Signal</title><author><name sortKey="Plant, Ewan P" sort="Plant, Ewan P" uniqKey="Plant E" first="Ewan P" last="Plant">Ewan P. Plant</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Perez Alvarado, Gabriela C" sort="Perez Alvarado, Gabriela C" uniqKey="Perez Alvarado G" first="Gabriela C" last="Pérez-Alvarado">Gabriela C. Pérez-Alvarado</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Jacobs, Jonathan L" sort="Jacobs, Jonathan L" uniqKey="Jacobs J" first="Jonathan L" last="Jacobs">Jonathan L. Jacobs</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Mukhopadhyay, Bani" sort="Mukhopadhyay, Bani" uniqKey="Mukhopadhyay B" first="Bani" last="Mukhopadhyay">Bani Mukhopadhyay</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hennig, Mirko" sort="Hennig, Mirko" uniqKey="Hennig M" first="Mirko" last="Hennig">Mirko Hennig</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Dinman, Jonathan D" sort="Dinman, Jonathan D" uniqKey="Dinman J" first="Jonathan D" last="Dinman">Jonathan D. Dinman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">15884978</idno><idno type="pmc">1110908</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1110908</idno><idno type="RBID">PMC:1110908</idno><idno type="doi">10.1371/journal.pbio.0030172</idno><date when="2005">2005</date><idno type="wicri:Area/Pmc/Corpus">001322</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001322</idno><idno type="wicri:Area/Pmc/Curation">001322</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001322</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Three-Stemmed mRNA Pseudoknot in the SARS Coronavirus Frameshift Signal</title><author><name sortKey="Plant, Ewan P" sort="Plant, Ewan P" uniqKey="Plant E" first="Ewan P" last="Plant">Ewan P. Plant</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Perez Alvarado, Gabriela C" sort="Perez Alvarado, Gabriela C" uniqKey="Perez Alvarado G" first="Gabriela C" last="Pérez-Alvarado">Gabriela C. Pérez-Alvarado</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Jacobs, Jonathan L" sort="Jacobs, Jonathan L" uniqKey="Jacobs J" first="Jonathan L" last="Jacobs">Jonathan L. Jacobs</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Mukhopadhyay, Bani" sort="Mukhopadhyay, Bani" uniqKey="Mukhopadhyay B" first="Bani" last="Mukhopadhyay">Bani Mukhopadhyay</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author><author><name sortKey="Hennig, Mirko" sort="Hennig, Mirko" uniqKey="Hennig M" first="Mirko" last="Hennig">Mirko Hennig</name><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Dinman, Jonathan D" sort="Dinman, Jonathan D" uniqKey="Dinman J" first="Jonathan D" last="Dinman">Jonathan D. Dinman</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Biology</title><idno type="ISSN">1544-9173</idno><idno type="eISSN">1545-7885</idno><imprint><date when="2005">2005</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>A wide range of RNA viruses use programmed −1 ribosomal frameshifting for the production of viral fusion proteins. Inspection of the overlap regions between ORF1a and ORF1b of the SARS-CoV genome revealed that, similar to all coronaviruses, a programmed −1 ribosomal frameshift could be used by the virus to produce a fusion protein. Computational analyses of the frameshift signal predicted the presence of an mRNA pseudoknot containing three double-stranded RNA stem structures rather than two. Phylogenetic analyses showed the conservation of potential three-stemmed pseudoknots in the frameshift signals of all other coronaviruses in the GenBank database. Though the presence of the three-stemmed structure is supported by nuclease mapping and two-dimensional nuclear magnetic resonance studies, our findings suggest that interactions between the stem structures may result in local distortions in the A-form RNA. These distortions are particularly evident in the vicinity of predicted A-bulges in stems 2 and 3. In vitro and in vivo frameshifting assays showed that the SARS-CoV frameshift signal is functionally similar to other viral frameshift signals: it promotes efficient frameshifting in all of the standard assay systems, and it is sensitive to a drug and a genetic mutation that are known to affect frameshifting efficiency of a yeast virus. Mutagenesis studies reveal that both the specific sequences and structures of stems 2 and 3 are important for efficient frameshifting. We have identified a new RNA structural motif that is capable of promoting efficient programmed ribosomal frameshifting. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Biol</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Biol</journal-id><journal-id journal-id-type="publisher-id">pbio</journal-id><journal-id journal-id-type="pmc">plosbiol</journal-id><journal-title-group><journal-title>PLoS Biology</journal-title></journal-title-group><issn pub-type="ppub">1544-9173</issn><issn pub-type="epub">1545-7885</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">15884978</article-id><article-id pub-id-type="pmc">1110908</article-id><article-id pub-id-type="doi">10.1371/journal.pbio.0030172</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Bioinformatics/Computational Biology</subject><subject>General Medicine</subject><subject>Respiratory Medicine</subject><subject>Statistics</subject><subject>Biochemistry</subject><subject>Biophysics</subject><subject>Cell Biology</subject><subject>Evolution</subject><subject>Genetics/Genomics/Gene Therapy</subject><subject>Infectious Diseases</subject><subject>Microbiology</subject><subject>Molecular Biology/Structural Biology</subject><subject>Virology</subject></subj-group><subj-group subj-group-type="System Taxonomy"><subject>Viruses</subject></subj-group></article-categories><title-group><article-title>A Three-Stemmed mRNA Pseudoknot in the SARS Coronavirus Frameshift Signal</article-title><alt-title alt-title-type="running-head">A New Frameshifting Pseudoknot in SARS</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Plant</surname><given-names>Ewan P</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pérez-Alvarado</surname><given-names>Gabriela C</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jacobs</surname><given-names>Jonathan L</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mukhopadhyay</surname><given-names>Bani</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hennig</surname><given-names>Mirko</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Dinman</surname><given-names>Jonathan D</given-names></name><email>dinman@umd.edu</email><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><bold>1</bold><institution>Department of Cell Biology and Molecular Genetics, University of Maryland</institution><addr-line>College Park, Maryland</addr-line><country>United States of America</country></aff><aff id="aff2"><bold>2</bold><institution>Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute</institution><addr-line>La Jolla, California</addr-line><country>United States of America</country></aff><contrib-group><contrib contrib-type="editor"><name><surname>Wickens</surname><given-names>Marv</given-names></name><role>Academic Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><institution>University of Wisconsin</institution><country>United States of America</country></aff><pub-date pub-type="ppub"><month>6</month><year>2005</year></pub-date><pub-date pub-type="epub"><day>17</day><month>5</month><year>2005</year></pub-date><pub-date pub-type="pmc-release"><day>17</day><month>5</month><year>2005</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>3</volume><issue>6</issue><elocation-id>e172</elocation-id><history><date date-type="received"><day>26</day><month>1</month><year>2005</year></date><date date-type="accepted"><day>14</day><month>3</month><year>2005</year></date></history><permissions><copyright-statement>Copyright: © 2005 Plant et al.</copyright-statement><copyright-year>2005</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><related-article id="d35e207" related-article-type="companion" ext-link-type="doi" xlink:href="10.1371/journal.pbio.0030199" xlink:title="synopsis" vol="3" page="e199"><article-title>New Frameshifting Pseudoknot Found in SARS Virus</article-title></related-article><related-article id="d35e212" related-article-type="companion" ext-link-type="doi" xlink:href="10.1371/journal.pbio.0030213" xlink:title="primer" vol="3" page="e213"><article-title>Pseudoknots: RNA Structures with Diverse Functions</article-title></related-article><abstract><p>A wide range of RNA viruses use programmed −1 ribosomal frameshifting for the production of viral fusion proteins. Inspection of the overlap regions between ORF1a and ORF1b of the SARS-CoV genome revealed that, similar to all coronaviruses, a programmed −1 ribosomal frameshift could be used by the virus to produce a fusion protein. Computational analyses of the frameshift signal predicted the presence of an mRNA pseudoknot containing three double-stranded RNA stem structures rather than two. Phylogenetic analyses showed the conservation of potential three-stemmed pseudoknots in the frameshift signals of all other coronaviruses in the GenBank database. Though the presence of the three-stemmed structure is supported by nuclease mapping and two-dimensional nuclear magnetic resonance studies, our findings suggest that interactions between the stem structures may result in local distortions in the A-form RNA. These distortions are particularly evident in the vicinity of predicted A-bulges in stems 2 and 3. In vitro and in vivo frameshifting assays showed that the SARS-CoV frameshift signal is functionally similar to other viral frameshift signals: it promotes efficient frameshifting in all of the standard assay systems, and it is sensitive to a drug and a genetic mutation that are known to affect frameshifting efficiency of a yeast virus. Mutagenesis studies reveal that both the specific sequences and structures of stems 2 and 3 are important for efficient frameshifting. We have identified a new RNA structural motif that is capable of promoting efficient programmed ribosomal frameshifting. The high degree of conservation of three-stemmed mRNA pseudoknot structures among the coronaviruses suggests that this presents a novel target for antiviral therapeutics.</p></abstract><abstract abstract-type="toc"><p>A new structural and conserved element is identified within the SARS virus genome. The element is important for gene expression, and might be a useful target for antiviral drugs.</p></abstract></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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