Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses.
Identifieur interne : 000E26 ( PubMed/Checkpoint ); précédent : 000E25; suivant : 000E27Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses.
Auteurs : Kathleen C. Lehmann [Pays-Bas] ; Anastasia Gulyaeva [Pays-Bas] ; Jessika C. Zevenhoven-Dobbe [Pays-Bas] ; George M C. Janssen [Pays-Bas] ; Mark Ruben [Pays-Bas] ; Hermen S. Overkleeft [Pays-Bas] ; Peter A. Van Veelen [Pays-Bas] ; Dmitry V. Samborskiy [Russie] ; Alexander A. Kravchenko [Russie] ; Andrey M. Leontovich [Russie] ; Igor A. Sidorov [Pays-Bas] ; Eric J. Snijder [Pays-Bas] ; Clara C. Posthuma [Pays-Bas] ; Alexander E. Gorbalenya [Pays-Bas]Source :
- Nucleic acids research [ 1362-4962 ] ; 2015.
Descripteurs français
- KwdFr :
- Guanosine (), Guanosine triphosphate (métabolisme), Manganèse (), Nidovirales (enzymologie), Nidovirales (génétique), Nucleotidyltransferases (), Nucleotidyltransferases (métabolisme), Nucléotides (métabolisme), Phosphates (), Polyprotéines (), Polyprotéines (métabolisme), Protéines virales (), Protéines virales (génétique), Protéines virales (métabolisme), RNA replicase (), RNA replicase (génétique), RNA replicase (métabolisme), Réplication virale, Sites de fixation, Structure tertiaire des protéines, Séquence conservée, Uridine (), Uridine triphosphate (métabolisme), Virus du SRAS (enzymologie), Virus du SRAS (physiologie).
- MESH :
- enzymologie : Nidovirales, Virus du SRAS.
- génétique : Nidovirales, Protéines virales, RNA replicase.
- métabolisme : Guanosine triphosphate, Nucleotidyltransferases, Nucléotides, Polyprotéines, Protéines virales, RNA replicase, Uridine triphosphate.
- physiologie : Virus du SRAS.
- Guanosine, Manganèse, Nucleotidyltransferases, Phosphates, Polyprotéines, Protéines virales, RNA replicase, Réplication virale, Sites de fixation, Structure tertiaire des protéines, Séquence conservée, Uridine.
English descriptors
- KwdEn :
- Binding Sites, Conserved Sequence, Equartevirus (enzymology), Equartevirus (physiology), Guanosine (chemistry), Guanosine Triphosphate (metabolism), Manganese (chemistry), Nidovirales (enzymology), Nidovirales (genetics), Nucleotides (metabolism), Nucleotidyltransferases (chemistry), Nucleotidyltransferases (metabolism), Phosphates (chemistry), Polyproteins (chemistry), Polyproteins (metabolism), Protein Structure, Tertiary, RNA Replicase (chemistry), RNA Replicase (genetics), RNA Replicase (metabolism), SARS Virus (enzymology), SARS Virus (physiology), Uridine (chemistry), Uridine Triphosphate (metabolism), Viral Proteins (chemistry), Viral Proteins (genetics), Viral Proteins (metabolism), Virus Replication.
- MESH :
- chemical , chemistry : Guanosine, Manganese, Nucleotidyltransferases, Phosphates, Polyproteins, RNA Replicase, Uridine, Viral Proteins.
- enzymology : Equartevirus, Nidovirales, SARS Virus.
- genetics : Nidovirales, RNA Replicase, Viral Proteins.
- chemical , metabolism : Guanosine Triphosphate, Nucleotides, Nucleotidyltransferases, Polyproteins, RNA Replicase, Uridine Triphosphate, Viral Proteins.
- physiology : Equartevirus, SARS Virus.
- Binding Sites, Conserved Sequence, Protein Structure, Tertiary, Virus Replication.
Abstract
RNA viruses encode an RNA-dependent RNA polymerase (RdRp) that catalyzes the synthesis of their RNA(s). In the case of positive-stranded RNA viruses belonging to the order Nidovirales, the RdRp resides in a replicase subunit that is unusually large. Bioinformatics analysis of this non-structural protein has now revealed a nidoviral signature domain (genetic marker) that is N-terminally adjacent to the RdRp and has no apparent homologs elsewhere. Based on its conservation profile, this domain is proposed to have nucleotidylation activity. We used recombinant non-structural protein 9 of the arterivirus equine arteritis virus (EAV) and different biochemical assays, including irreversible labeling with a GTP analog followed by a proteomics analysis, to demonstrate the manganese-dependent covalent binding of guanosine and uridine phosphates to a lysine/histidine residue. Most likely this was the invariant lysine of the newly identified domain, named nidovirus RdRp-associated nucleotidyltransferase (NiRAN), whose substitution with alanine severely diminished the described binding. Furthermore, this mutation crippled EAV and prevented the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in cell culture, indicating that NiRAN is essential for nidoviruses. Potential functions supported by NiRAN may include nucleic acid ligation, mRNA capping and protein-primed RNA synthesis, possibilities that remain to be explored in future studies.
DOI: 10.1093/nar/gkv838
PubMed: 26304538
Affiliations:
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Posthuma</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Gorbalenya, Alexander E" sort="Gorbalenya, Alexander E" uniqKey="Gorbalenya A" first="Alexander E" last="Gorbalenya">Alexander E. Gorbalenya</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow, Russia a.e.gorbalenya@lumc.nl.</nlm:affiliation><country wicri:rule="url">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow</wicri:regionArea><wicri:noRegion>119899 Moscow</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2015">2015</date><idno type="RBID">pubmed:26304538</idno><idno type="pmid">26304538</idno><idno type="doi">10.1093/nar/gkv838</idno><idno type="wicri:Area/PubMed/Corpus">000D79</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000D79</idno><idno type="wicri:Area/PubMed/Curation">000D79</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000D79</idno><idno type="wicri:Area/PubMed/Checkpoint">000E26</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000E26</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses.</title><author><name sortKey="Lehmann, Kathleen C" sort="Lehmann, Kathleen C" uniqKey="Lehmann K" first="Kathleen C" last="Lehmann">Kathleen C. Lehmann</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Gulyaeva, Anastasia" sort="Gulyaeva, Anastasia" uniqKey="Gulyaeva A" first="Anastasia" last="Gulyaeva">Anastasia Gulyaeva</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Zevenhoven Dobbe, Jessika C" sort="Zevenhoven Dobbe, Jessika C" uniqKey="Zevenhoven Dobbe J" first="Jessika C" last="Zevenhoven-Dobbe">Jessika C. Zevenhoven-Dobbe</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Janssen, George M C" sort="Janssen, George M C" uniqKey="Janssen G" first="George M C" last="Janssen">George M C. Janssen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Ruben, Mark" sort="Ruben, Mark" uniqKey="Ruben M" first="Mark" last="Ruben">Mark Ruben</name><affiliation wicri:level="3"><nlm:affiliation>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Overkleeft, Hermen S" sort="Overkleeft, Hermen S" uniqKey="Overkleeft H" first="Hermen S" last="Overkleeft">Hermen S. Overkleeft</name><affiliation wicri:level="3"><nlm:affiliation>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Van Veelen, Peter A" sort="Van Veelen, Peter A" uniqKey="Van Veelen P" first="Peter A" last="Van Veelen">Peter A. Van Veelen</name><affiliation wicri:level="3"><nlm:affiliation>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Samborskiy, Dmitry V" sort="Samborskiy, Dmitry V" uniqKey="Samborskiy D" first="Dmitry V" last="Samborskiy">Dmitry V. Samborskiy</name><affiliation wicri:level="1"><nlm:affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Kravchenko, Alexander A" sort="Kravchenko, Alexander A" uniqKey="Kravchenko A" first="Alexander A" last="Kravchenko">Alexander A. Kravchenko</name><affiliation wicri:level="1"><nlm:affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Leontovich, Andrey M" sort="Leontovich, Andrey M" uniqKey="Leontovich A" first="Andrey M" last="Leontovich">Andrey M. Leontovich</name><affiliation wicri:level="1"><nlm:affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</nlm:affiliation><country xml:lang="fr">Russie</country><wicri:regionArea>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow</wicri:regionArea><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation></author><author><name sortKey="Sidorov, Igor A" sort="Sidorov, Igor A" uniqKey="Sidorov I" first="Igor A" last="Sidorov">Igor A. Sidorov</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Snijder, Eric J" sort="Snijder, Eric J" uniqKey="Snijder E" first="Eric J" last="Snijder">Eric J. Snijder</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Posthuma, Clara C" sort="Posthuma, Clara C" uniqKey="Posthuma C" first="Clara C" last="Posthuma">Clara C. Posthuma</name><affiliation wicri:level="3"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</nlm:affiliation><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden</wicri:regionArea><placeName><settlement type="city">Leyde</settlement><region nuts="2" type="province">Hollande-Méridionale</region></placeName></affiliation></author><author><name sortKey="Gorbalenya, Alexander E" sort="Gorbalenya, Alexander E" uniqKey="Gorbalenya A" first="Alexander E" last="Gorbalenya">Alexander E. Gorbalenya</name><affiliation wicri:level="1"><nlm:affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow, Russia a.e.gorbalenya@lumc.nl.</nlm:affiliation><country wicri:rule="url">Pays-Bas</country><wicri:regionArea>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow</wicri:regionArea><wicri:noRegion>119899 Moscow</wicri:noRegion></affiliation></author></analytic><series><title level="j">Nucleic acids research</title><idno type="eISSN">1362-4962</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Binding Sites</term><term>Conserved Sequence</term><term>Equartevirus (enzymology)</term><term>Equartevirus (physiology)</term><term>Guanosine (chemistry)</term><term>Guanosine Triphosphate (metabolism)</term><term>Manganese (chemistry)</term><term>Nidovirales (enzymology)</term><term>Nidovirales (genetics)</term><term>Nucleotides (metabolism)</term><term>Nucleotidyltransferases (chemistry)</term><term>Nucleotidyltransferases (metabolism)</term><term>Phosphates (chemistry)</term><term>Polyproteins (chemistry)</term><term>Polyproteins (metabolism)</term><term>Protein Structure, Tertiary</term><term>RNA Replicase (chemistry)</term><term>RNA Replicase (genetics)</term><term>RNA Replicase (metabolism)</term><term>SARS Virus (enzymology)</term><term>SARS Virus (physiology)</term><term>Uridine (chemistry)</term><term>Uridine Triphosphate (metabolism)</term><term>Viral Proteins (chemistry)</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Guanosine ()</term><term>Guanosine triphosphate (métabolisme)</term><term>Manganèse ()</term><term>Nidovirales (enzymologie)</term><term>Nidovirales (génétique)</term><term>Nucleotidyltransferases ()</term><term>Nucleotidyltransferases (métabolisme)</term><term>Nucléotides (métabolisme)</term><term>Phosphates ()</term><term>Polyprotéines ()</term><term>Polyprotéines (métabolisme)</term><term>Protéines virales ()</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>RNA replicase ()</term><term>RNA replicase (génétique)</term><term>RNA replicase (métabolisme)</term><term>Réplication virale</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence conservée</term><term>Uridine ()</term><term>Uridine triphosphate (métabolisme)</term><term>Virus du SRAS (enzymologie)</term><term>Virus du SRAS (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Guanosine</term><term>Manganese</term><term>Nucleotidyltransferases</term><term>Phosphates</term><term>Polyproteins</term><term>RNA Replicase</term><term>Uridine</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Nidovirales</term><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Equartevirus</term><term>Nidovirales</term><term>SARS Virus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Nidovirales</term><term>RNA Replicase</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Nidovirales</term><term>Protéines virales</term><term>RNA replicase</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Guanosine Triphosphate</term><term>Nucleotides</term><term>Nucleotidyltransferases</term><term>Polyproteins</term><term>RNA Replicase</term><term>Uridine Triphosphate</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Guanosine triphosphate</term><term>Nucleotidyltransferases</term><term>Nucléotides</term><term>Polyprotéines</term><term>Protéines virales</term><term>RNA replicase</term><term>Uridine triphosphate</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Virus du SRAS</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Equartevirus</term><term>SARS Virus</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Binding Sites</term><term>Conserved Sequence</term><term>Protein Structure, Tertiary</term><term>Virus Replication</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Guanosine</term><term>Manganèse</term><term>Nucleotidyltransferases</term><term>Phosphates</term><term>Polyprotéines</term><term>Protéines virales</term><term>RNA replicase</term><term>Réplication virale</term><term>Sites de fixation</term><term>Structure tertiaire des protéines</term><term>Séquence conservée</term><term>Uridine</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">RNA viruses encode an RNA-dependent RNA polymerase (RdRp) that catalyzes the synthesis of their RNA(s). In the case of positive-stranded RNA viruses belonging to the order Nidovirales, the RdRp resides in a replicase subunit that is unusually large. Bioinformatics analysis of this non-structural protein has now revealed a nidoviral signature domain (genetic marker) that is N-terminally adjacent to the RdRp and has no apparent homologs elsewhere. Based on its conservation profile, this domain is proposed to have nucleotidylation activity. We used recombinant non-structural protein 9 of the arterivirus equine arteritis virus (EAV) and different biochemical assays, including irreversible labeling with a GTP analog followed by a proteomics analysis, to demonstrate the manganese-dependent covalent binding of guanosine and uridine phosphates to a lysine/histidine residue. Most likely this was the invariant lysine of the newly identified domain, named nidovirus RdRp-associated nucleotidyltransferase (NiRAN), whose substitution with alanine severely diminished the described binding. Furthermore, this mutation crippled EAV and prevented the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in cell culture, indicating that NiRAN is essential for nidoviruses. Potential functions supported by NiRAN may include nucleic acid ligation, mRNA capping and protein-primed RNA synthesis, possibilities that remain to be explored in future studies. </div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26304538</PMID><DateCompleted><Year>2016</Year><Month>01</Month><Day>11</Day></DateCompleted><DateRevised><Year>2018</Year><Month>12</Month><Day>02</Day></DateRevised><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1362-4962</ISSN><JournalIssue CitedMedium="Internet"><Volume>43</Volume><Issue>17</Issue><PubDate><Year>2015</Year><Month>Sep</Month><Day>30</Day></PubDate></JournalIssue><Title>Nucleic acids research</Title><ISOAbbreviation>Nucleic Acids Res.</ISOAbbreviation></Journal><ArticleTitle>Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses.</ArticleTitle><Pagination><MedlinePgn>8416-34</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1093/nar/gkv838</ELocationID><Abstract><AbstractText>RNA viruses encode an RNA-dependent RNA polymerase (RdRp) that catalyzes the synthesis of their RNA(s). In the case of positive-stranded RNA viruses belonging to the order Nidovirales, the RdRp resides in a replicase subunit that is unusually large. Bioinformatics analysis of this non-structural protein has now revealed a nidoviral signature domain (genetic marker) that is N-terminally adjacent to the RdRp and has no apparent homologs elsewhere. Based on its conservation profile, this domain is proposed to have nucleotidylation activity. We used recombinant non-structural protein 9 of the arterivirus equine arteritis virus (EAV) and different biochemical assays, including irreversible labeling with a GTP analog followed by a proteomics analysis, to demonstrate the manganese-dependent covalent binding of guanosine and uridine phosphates to a lysine/histidine residue. Most likely this was the invariant lysine of the newly identified domain, named nidovirus RdRp-associated nucleotidyltransferase (NiRAN), whose substitution with alanine severely diminished the described binding. Furthermore, this mutation crippled EAV and prevented the replication of severe acute respiratory syndrome coronavirus (SARS-CoV) in cell culture, indicating that NiRAN is essential for nidoviruses. Potential functions supported by NiRAN may include nucleic acid ligation, mRNA capping and protein-primed RNA synthesis, possibilities that remain to be explored in future studies. </AbstractText><CopyrightInformation>© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Lehmann</LastName><ForeName>Kathleen C</ForeName><Initials>KC</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gulyaeva</LastName><ForeName>Anastasia</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Zevenhoven-Dobbe</LastName><ForeName>Jessika C</ForeName><Initials>JC</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Janssen</LastName><ForeName>George M C</ForeName><Initials>GM</Initials><AffiliationInfo><Affiliation>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Ruben</LastName><ForeName>Mark</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Overkleeft</LastName><ForeName>Hermen S</ForeName><Initials>HS</Initials><AffiliationInfo><Affiliation>Leiden Institute of Chemistry, Leiden University, 2300 CC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>van Veelen</LastName><ForeName>Peter A</ForeName><Initials>PA</Initials><AffiliationInfo><Affiliation>Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Samborskiy</LastName><ForeName>Dmitry V</ForeName><Initials>DV</Initials><AffiliationInfo><Affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kravchenko</LastName><ForeName>Alexander A</ForeName><Initials>AA</Initials><AffiliationInfo><Affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leontovich</LastName><ForeName>Andrey M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Sidorov</LastName><ForeName>Igor A</ForeName><Initials>IA</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Snijder</LastName><ForeName>Eric J</ForeName><Initials>EJ</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Posthuma</LastName><ForeName>Clara C</ForeName><Initials>CC</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gorbalenya</LastName><ForeName>Alexander E</ForeName><Initials>AE</Initials><AffiliationInfo><Affiliation>Department of Medical Microbiology, Leiden University Medical Center, Leiden, 2300 RC, Leiden, The Netherlands Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119899 Moscow, Russia Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119899 Moscow, Russia a.e.gorbalenya@lumc.nl.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>08</Month><Day>24</Day></ArticleDate></Article><MedlineJournalInfo><Country>England</Country><MedlineTA>Nucleic Acids Res</MedlineTA><NlmUniqueID>0411011</NlmUniqueID><ISSNLinking>0305-1048</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D009711">Nucleotides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D010710">Phosphates</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D020815">Polyproteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014764">Viral Proteins</NameOfSubstance></Chemical><Chemical><RegistryNumber>12133JR80S</RegistryNumber><NameOfSubstance UI="D006151">Guanosine</NameOfSubstance></Chemical><Chemical><RegistryNumber>42Z2K6ZL8P</RegistryNumber><NameOfSubstance UI="D008345">Manganese</NameOfSubstance></Chemical><Chemical><RegistryNumber>86-01-1</RegistryNumber><NameOfSubstance UI="D006160">Guanosine Triphosphate</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.7.-</RegistryNumber><NameOfSubstance UI="D009713">Nucleotidyltransferases</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 2.7.7.48</RegistryNumber><NameOfSubstance UI="D012324">RNA Replicase</NameOfSubstance></Chemical><Chemical><RegistryNumber>UT0S826Z60</RegistryNumber><NameOfSubstance UI="D014544">Uridine Triphosphate</NameOfSubstance></Chemical><Chemical><RegistryNumber>WHI7HQ7H85</RegistryNumber><NameOfSubstance UI="D014529">Uridine</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D001665" MajorTopicYN="N">Binding Sites</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017124" MajorTopicYN="N">Conserved Sequence</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D007240" MajorTopicYN="N">Equartevirus</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006151" MajorTopicYN="N">Guanosine</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006160" MajorTopicYN="N">Guanosine Triphosphate</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008345" MajorTopicYN="N">Manganese</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D028381" MajorTopicYN="N">Nidovirales</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="Y">enzymology</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009711" MajorTopicYN="N">Nucleotides</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D009713" MajorTopicYN="N">Nucleotidyltransferases</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D010710" MajorTopicYN="N">Phosphates</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D020815" MajorTopicYN="N">Polyproteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D017434" MajorTopicYN="N">Protein Structure, Tertiary</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D012324" MajorTopicYN="N">RNA Replicase</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D045473" MajorTopicYN="N">SARS Virus</DescriptorName><QualifierName UI="Q000201" MajorTopicYN="N">enzymology</QualifierName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014529" MajorTopicYN="N">Uridine</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014544" MajorTopicYN="N">Uridine Triphosphate</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014764" MajorTopicYN="N">Viral Proteins</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="Y">chemistry</QualifierName><QualifierName UI="Q000235" MajorTopicYN="N">genetics</QualifierName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D014779" MajorTopicYN="N">Virus 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