Molecular mapping of the RNA Cap 2'-O-methyltransferase activation interface between severe acute respiratory syndrome coronavirus nsp10 and nsp16.
Identifieur interne : 000216 ( France/Analysis ); précédent : 000215; suivant : 000217Molecular mapping of the RNA Cap 2'-O-methyltransferase activation interface between severe acute respiratory syndrome coronavirus nsp10 and nsp16.
Auteurs : Adrien Lugari [France] ; Stephane Betzi ; Etienne Decroly ; Emmanuel Bonnaud ; Aurélie Hermant ; Jean-Claude Guillemot ; Claire Debarnot ; Jean-Paul Borg ; Mickaël Bouvet ; Bruno Canard ; Xavier Morelli ; Patrick LécineSource :
- The Journal of biological chemistry [ 1083-351X ] ; 2010.
Descripteurs français
- KwdFr :
- Activation enzymatique, Humains, Lignée cellulaire, Methyltransferases (génétique), Methyltransferases (métabolisme), Mutagenèse, Mutation faux-sens, Protéines virales non structurales (génétique), Protéines virales non structurales (métabolisme), Virus du SRAS (génétique), Virus du SRAS (métabolisme).
- MESH :
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : Methyltransferases, Viral Nonstructural Proteins.
- chemical , metabolism : Methyltransferases, Viral Nonstructural Proteins.
- genetics : SARS Virus.
- metabolism : SARS Virus.
- Cell Line, Enzyme Activation, Humans, Mutagenesis, Mutation, Missense.
Abstract
Several protein-protein interactions within the SARS-CoV proteome have been identified, one of them being between non-structural proteins nsp10 and nsp16. In this work, we have mapped key residues on the nsp10 surface involved in this interaction. Alanine-scanning mutagenesis, bioinformatics, and molecular modeling were used to identify several "hot spots," such as Val(42), Met(44), Ala(71), Lys(93), Gly(94), and Tyr(96), forming a continuous protein-protein surface of about 830 Å(2), bearing very conserved amino acids among coronaviruses. Because nsp16 carries RNA cap 2'-O-methyltransferase (2'O-MTase) activity only in the presence of its interacting partner nsp10 (Bouvet, M., Debarnot, C., Imbert, I., Selisko, B., Snijder, E. J., Canard, B., and Decroly, E. (2010) PLoS Pathog. 6, e1000863), functional consequences of mutations on this surface were evaluated biochemically. Most changes that disrupted the nsp10-nsp16 interaction without structural perturbations were shown to abrogate stimulation of nsp16 RNA cap 2'O-MTase activity. More strikingly, the Y96A mutation abrogates stimulation of nsp16 2'O-MTase activity, whereas Y96F overstimulates it. Thus, the nsp10-nsp16 interface may represent an attractive target for antivirals against human and animal pathogenic coronaviruses.
DOI: 10.1074/jbc.M110.120014
PubMed: 20699222
Affiliations:
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pubmed:20699222Le document en format XML
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Lugari</name><affiliation wicri:level="3"><nlm:affiliation>IMR Laboratory, UPR 3243, Institut de Microbiologie de la Méditérannée, CNRS and Aix-Marseille Universités, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>IMR Laboratory, UPR 3243, Institut de Microbiologie de la Méditérannée, CNRS and Aix-Marseille Universités, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20</wicri:regionArea><placeName><region type="region" nuts="2">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation></author><author><name sortKey="Betzi, Stephane" sort="Betzi, Stephane" uniqKey="Betzi S" first="Stephane" last="Betzi">Stephane Betzi</name></author><author><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name></author><author><name sortKey="Bonnaud, Emmanuel" sort="Bonnaud, Emmanuel" 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enzymatique</term><term>Humains</term><term>Lignée cellulaire</term><term>Methyltransferases (génétique)</term><term>Methyltransferases (métabolisme)</term><term>Mutagenèse</term><term>Mutation faux-sens</term><term>Protéines virales non structurales (génétique)</term><term>Protéines virales non structurales (métabolisme)</term><term>Virus du SRAS (génétique)</term><term>Virus du SRAS (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Methyltransferases</term><term>Viral Nonstructural Proteins</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Methyltransferases</term><term>Protéines virales non structurales</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Methyltransferases</term><term>Protéines virales non structurales</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Cell Line</term><term>Enzyme Activation</term><term>Humans</term><term>Mutagenesis</term><term>Mutation, Missense</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Activation enzymatique</term><term>Humains</term><term>Lignée cellulaire</term><term>Mutagenèse</term><term>Mutation faux-sens</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Several protein-protein interactions within the SARS-CoV proteome have been identified, one of them being between non-structural proteins nsp10 and nsp16. In this work, we have mapped key residues on the nsp10 surface involved in this interaction. Alanine-scanning mutagenesis, bioinformatics, and molecular modeling were used to identify several "hot spots," such as Val(42), Met(44), Ala(71), Lys(93), Gly(94), and Tyr(96), forming a continuous protein-protein surface of about 830 Å(2), bearing very conserved amino acids among coronaviruses. Because nsp16 carries RNA cap 2'-O-methyltransferase (2'O-MTase) activity only in the presence of its interacting partner nsp10 (Bouvet, M., Debarnot, C., Imbert, I., Selisko, B., Snijder, E. J., Canard, B., and Decroly, E. (2010) PLoS Pathog. 6, e1000863), functional consequences of mutations on this surface were evaluated biochemically. Most changes that disrupted the nsp10-nsp16 interaction without structural perturbations were shown to abrogate stimulation of nsp16 RNA cap 2'O-MTase activity. More strikingly, the Y96A mutation abrogates stimulation of nsp16 2'O-MTase activity, whereas Y96F overstimulates it. Thus, the nsp10-nsp16 interface may represent an attractive target for antivirals against human and animal pathogenic coronaviruses.</div></front></TEI><affiliations><list><country><li>France</li></country><region><li>Provence-Alpes-Côte d'Azur</li></region><settlement><li>Marseille</li></settlement></list><tree><noCountry><name sortKey="Betzi, Stephane" sort="Betzi, Stephane" uniqKey="Betzi S" first="Stephane" last="Betzi">Stephane Betzi</name><name sortKey="Bonnaud, Emmanuel" sort="Bonnaud, Emmanuel" uniqKey="Bonnaud E" first="Emmanuel" last="Bonnaud">Emmanuel Bonnaud</name><name sortKey="Borg, Jean Paul" sort="Borg, Jean Paul" uniqKey="Borg J" first="Jean-Paul" last="Borg">Jean-Paul Borg</name><name sortKey="Bouvet, Mickael" sort="Bouvet, Mickael" uniqKey="Bouvet M" first="Mickaël" last="Bouvet">Mickaël Bouvet</name><name sortKey="Canard, Bruno" sort="Canard, Bruno" uniqKey="Canard B" first="Bruno" last="Canard">Bruno Canard</name><name sortKey="Debarnot, Claire" sort="Debarnot, Claire" uniqKey="Debarnot C" first="Claire" last="Debarnot">Claire Debarnot</name><name sortKey="Decroly, Etienne" sort="Decroly, Etienne" uniqKey="Decroly E" first="Etienne" last="Decroly">Etienne Decroly</name><name sortKey="Guillemot, Jean Claude" sort="Guillemot, Jean Claude" uniqKey="Guillemot J" first="Jean-Claude" last="Guillemot">Jean-Claude Guillemot</name><name sortKey="Hermant, Aurelie" sort="Hermant, Aurelie" uniqKey="Hermant A" first="Aurélie" last="Hermant">Aurélie Hermant</name><name sortKey="Lecine, Patrick" sort="Lecine, Patrick" uniqKey="Lecine P" first="Patrick" last="Lécine">Patrick Lécine</name><name sortKey="Morelli, Xavier" sort="Morelli, Xavier" uniqKey="Morelli X" first="Xavier" last="Morelli">Xavier Morelli</name></noCountry><country name="France"><region name="Provence-Alpes-Côte d'Azur"><name sortKey="Lugari, Adrien" sort="Lugari, Adrien" uniqKey="Lugari A" first="Adrien" last="Lugari">Adrien Lugari</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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