Structural basis for tRNA methylthiolation by the radical SAM enzyme MiaB

Numerous post-transcriptional modifications of transfer RNAs have vital roles in translation. The 2-methylthio- N 6 -isopentenyladenosine (ms 2 i 6 A) modification occurs at position 37 (A37) in transfer RNAs that contain adenine in position 36 of the anticodon, and serves to promote efficient A:U c...

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Veröffentlicht in:Nature (London) 2021-09, Vol.597 (7877), p.566-570
Hauptverfasser: Esakova, Olga A., Grove, Tyler L., Yennawar, Neela H., Arcinas, Arthur J., Wang, Bo, Krebs, Carsten, Almo, Steven C., Booker, Squire J.
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container_end_page 570
container_issue 7877
container_start_page 566
container_title Nature (London)
container_volume 597
creator Esakova, Olga A.
Grove, Tyler L.
Yennawar, Neela H.
Arcinas, Arthur J.
Wang, Bo
Krebs, Carsten
Almo, Steven C.
Booker, Squire J.
description Numerous post-transcriptional modifications of transfer RNAs have vital roles in translation. The 2-methylthio- N 6 -isopentenyladenosine (ms 2 i 6 A) modification occurs at position 37 (A37) in transfer RNAs that contain adenine in position 36 of the anticodon, and serves to promote efficient A:U codon–anticodon base-pairing and to prevent unintended base pairing by near cognates, thus enhancing translational fidelity 1 – 4 . The ms 2 i 6 A modification is installed onto isopentenyladenosine (i 6 A) by MiaB, a radical S -adenosylmethionine (SAM) methylthiotransferase. As a radical SAM protein, MiaB contains one [Fe 4 S 4 ] RS cluster used in the reductive cleavage of SAM to form a 5ʹ-deoxyadenosyl 5ʹ-radical, which is responsible for removing the C 2 hydrogen of the substrate 5 . MiaB also contains an auxiliary [Fe 4 S 4 ] aux cluster, which has been implicated 6 – 9 in sulfur transfer to C 2 of i 6 A37. How this transfer takes place is largely unknown. Here we present several structures of MiaB from Bacteroides uniformis . These structures are consistent with a two-step mechanism, in which one molecule of SAM is first used to methylate a bridging µ-sulfido ion of the auxiliary cluster. In the second step, a second SAM molecule is cleaved to a 5ʹ-deoxyadenosyl 5ʹ-radical, which abstracts the C 2 hydrogen of the substrate but only after C 2 has undergone rehybridization from sp 2 to sp 3 . This work advances our understanding of how enzymes functionalize inert C–H bonds with sulfur. Crystal structures reveal the catalytic mechanism through which the radical S -adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.
doi_str_mv 10.1038/s41586-021-03904-6
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The 2-methylthio- N 6 -isopentenyladenosine (ms 2 i 6 A) modification occurs at position 37 (A37) in transfer RNAs that contain adenine in position 36 of the anticodon, and serves to promote efficient A:U codon–anticodon base-pairing and to prevent unintended base pairing by near cognates, thus enhancing translational fidelity 1 – 4 . The ms 2 i 6 A modification is installed onto isopentenyladenosine (i 6 A) by MiaB, a radical S -adenosylmethionine (SAM) methylthiotransferase. As a radical SAM protein, MiaB contains one [Fe 4 S 4 ] RS cluster used in the reductive cleavage of SAM to form a 5ʹ-deoxyadenosyl 5ʹ-radical, which is responsible for removing the C 2 hydrogen of the substrate 5 . MiaB also contains an auxiliary [Fe 4 S 4 ] aux cluster, which has been implicated 6 – 9 in sulfur transfer to C 2 of i 6 A37. How this transfer takes place is largely unknown. Here we present several structures of MiaB from Bacteroides uniformis . These structures are consistent with a two-step mechanism, in which one molecule of SAM is first used to methylate a bridging µ-sulfido ion of the auxiliary cluster. In the second step, a second SAM molecule is cleaved to a 5ʹ-deoxyadenosyl 5ʹ-radical, which abstracts the C 2 hydrogen of the substrate but only after C 2 has undergone rehybridization from sp 2 to sp 3 . This work advances our understanding of how enzymes functionalize inert C–H bonds with sulfur. Crystal structures reveal the catalytic mechanism through which the radical S -adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03904-6</identifier><identifier>PMID: 34526715</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/45/49/1141 ; 631/535/1266 ; 82/80 ; 82/83 ; Adenine ; Adenosine ; Adenosine - analogs &amp; derivatives ; Adenosine - metabolism ; Adenosylmethionine ; Bacteroides - enzymology ; Binding Sites ; Biocatalysis ; Clusters ; Cyclin-dependent kinases ; Enzymes ; Genetic aspects ; Humanities and Social Sciences ; Hydrogen ; Isopentenyladenosine - metabolism ; Methyltransferases - chemistry ; Methyltransferases - metabolism ; Models, Molecular ; multidisciplinary ; Oxygen ; Physiological aspects ; Post-transcription ; Protein Domains ; Proteins ; Radicals ; RNA - metabolism ; RNA, Transfer - chemistry ; RNA, Transfer - metabolism ; RNA-Binding Proteins - chemistry ; RNA-Binding Proteins - metabolism ; S-Adenosylmethionine - metabolism ; Science ; Science (multidisciplinary) ; Structure ; Substrate Specificity ; Substrates ; Sulfhydryl Compounds - metabolism ; Sulfur ; Sulfurtransferases - chemistry ; Sulfurtransferases - metabolism ; Transfer RNA ; tRNA</subject><ispartof>Nature (London), 2021-09, Vol.597 (7877), p.566-570</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. 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The 2-methylthio- N 6 -isopentenyladenosine (ms 2 i 6 A) modification occurs at position 37 (A37) in transfer RNAs that contain adenine in position 36 of the anticodon, and serves to promote efficient A:U codon–anticodon base-pairing and to prevent unintended base pairing by near cognates, thus enhancing translational fidelity 1 – 4 . The ms 2 i 6 A modification is installed onto isopentenyladenosine (i 6 A) by MiaB, a radical S -adenosylmethionine (SAM) methylthiotransferase. As a radical SAM protein, MiaB contains one [Fe 4 S 4 ] RS cluster used in the reductive cleavage of SAM to form a 5ʹ-deoxyadenosyl 5ʹ-radical, which is responsible for removing the C 2 hydrogen of the substrate 5 . MiaB also contains an auxiliary [Fe 4 S 4 ] aux cluster, which has been implicated 6 – 9 in sulfur transfer to C 2 of i 6 A37. How this transfer takes place is largely unknown. Here we present several structures of MiaB from Bacteroides uniformis . These structures are consistent with a two-step mechanism, in which one molecule of SAM is first used to methylate a bridging µ-sulfido ion of the auxiliary cluster. In the second step, a second SAM molecule is cleaved to a 5ʹ-deoxyadenosyl 5ʹ-radical, which abstracts the C 2 hydrogen of the substrate but only after C 2 has undergone rehybridization from sp 2 to sp 3 . This work advances our understanding of how enzymes functionalize inert C–H bonds with sulfur. Crystal structures reveal the catalytic mechanism through which the radical S -adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.</description><subject>631/45/49/1141</subject><subject>631/535/1266</subject><subject>82/80</subject><subject>82/83</subject><subject>Adenine</subject><subject>Adenosine</subject><subject>Adenosine - analogs &amp; derivatives</subject><subject>Adenosine - metabolism</subject><subject>Adenosylmethionine</subject><subject>Bacteroides - enzymology</subject><subject>Binding Sites</subject><subject>Biocatalysis</subject><subject>Clusters</subject><subject>Cyclin-dependent kinases</subject><subject>Enzymes</subject><subject>Genetic aspects</subject><subject>Humanities and Social Sciences</subject><subject>Hydrogen</subject><subject>Isopentenyladenosine - metabolism</subject><subject>Methyltransferases - chemistry</subject><subject>Methyltransferases - metabolism</subject><subject>Models, 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basis for tRNA methylthiolation by the radical SAM enzyme MiaB</title><author>Esakova, Olga A. ; Grove, Tyler L. ; Yennawar, Neela H. ; Arcinas, Arthur J. ; Wang, Bo ; Krebs, Carsten ; Almo, Steven C. ; Booker, Squire J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c742t-839f8a397c09ac3a83fbffa483ac25dfeef965cb0f9ebf4d1237f14f687f64793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>631/45/49/1141</topic><topic>631/535/1266</topic><topic>82/80</topic><topic>82/83</topic><topic>Adenine</topic><topic>Adenosine</topic><topic>Adenosine - analogs &amp; derivatives</topic><topic>Adenosine - metabolism</topic><topic>Adenosylmethionine</topic><topic>Bacteroides - enzymology</topic><topic>Binding Sites</topic><topic>Biocatalysis</topic><topic>Clusters</topic><topic>Cyclin-dependent kinases</topic><topic>Enzymes</topic><topic>Genetic aspects</topic><topic>Humanities and Social 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nature (London)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Esakova, Olga A.</au><au>Grove, Tyler L.</au><au>Yennawar, Neela H.</au><au>Arcinas, Arthur J.</au><au>Wang, Bo</au><au>Krebs, Carsten</au><au>Almo, Steven C.</au><au>Booker, Squire J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structural basis for tRNA methylthiolation by the radical SAM enzyme MiaB</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-09-23</date><risdate>2021</risdate><volume>597</volume><issue>7877</issue><spage>566</spage><epage>570</epage><pages>566-570</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Numerous post-transcriptional modifications of transfer RNAs have vital roles in translation. The 2-methylthio- N 6 -isopentenyladenosine (ms 2 i 6 A) modification occurs at position 37 (A37) in transfer RNAs that contain adenine in position 36 of the anticodon, and serves to promote efficient A:U codon–anticodon base-pairing and to prevent unintended base pairing by near cognates, thus enhancing translational fidelity 1 – 4 . The ms 2 i 6 A modification is installed onto isopentenyladenosine (i 6 A) by MiaB, a radical S -adenosylmethionine (SAM) methylthiotransferase. As a radical SAM protein, MiaB contains one [Fe 4 S 4 ] RS cluster used in the reductive cleavage of SAM to form a 5ʹ-deoxyadenosyl 5ʹ-radical, which is responsible for removing the C 2 hydrogen of the substrate 5 . MiaB also contains an auxiliary [Fe 4 S 4 ] aux cluster, which has been implicated 6 – 9 in sulfur transfer to C 2 of i 6 A37. How this transfer takes place is largely unknown. Here we present several structures of MiaB from Bacteroides uniformis . These structures are consistent with a two-step mechanism, in which one molecule of SAM is first used to methylate a bridging µ-sulfido ion of the auxiliary cluster. In the second step, a second SAM molecule is cleaved to a 5ʹ-deoxyadenosyl 5ʹ-radical, which abstracts the C 2 hydrogen of the substrate but only after C 2 has undergone rehybridization from sp 2 to sp 3 . This work advances our understanding of how enzymes functionalize inert C–H bonds with sulfur. Crystal structures reveal the catalytic mechanism through which the radical S -adenosylmethionine enzyme MiaB adds a methylthio group onto tRNA.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34526715</pmid><doi>10.1038/s41586-021-03904-6</doi><tpages>5</tpages><orcidid>https://orcid.org/0000-0001-8377-8368</orcidid><orcidid>https://orcid.org/0000-0003-2591-5234</orcidid><orcidid>https://orcid.org/0000-0002-7211-5937</orcidid><orcidid>https://orcid.org/0000-0002-4763-0646</orcidid><orcidid>https://orcid.org/0000-0003-4903-3500</orcidid><orcidid>https://orcid.org/0000-0001-7278-659X</orcidid><orcidid>https://orcid.org/0000-0002-0381-3686</orcidid><orcidid>https://orcid.org/0000-0002-3302-7053</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 0028-0836
ispartof Nature (London), 2021-09, Vol.597 (7877), p.566-570
issn 0028-0836
1476-4687
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9107155
source MEDLINE; Nature; Springer Nature - Complete Springer Journals
subjects 631/45/49/1141
631/535/1266
82/80
82/83
Adenine
Adenosine
Adenosine - analogs & derivatives
Adenosine - metabolism
Adenosylmethionine
Bacteroides - enzymology
Binding Sites
Biocatalysis
Clusters
Cyclin-dependent kinases
Enzymes
Genetic aspects
Humanities and Social Sciences
Hydrogen
Isopentenyladenosine - metabolism
Methyltransferases - chemistry
Methyltransferases - metabolism
Models, Molecular
multidisciplinary
Oxygen
Physiological aspects
Post-transcription
Protein Domains
Proteins
Radicals
RNA - metabolism
RNA, Transfer - chemistry
RNA, Transfer - metabolism
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
S-Adenosylmethionine - metabolism
Science
Science (multidisciplinary)
Structure
Substrate Specificity
Substrates
Sulfhydryl Compounds - metabolism
Sulfur
Sulfurtransferases - chemistry
Sulfurtransferases - metabolism
Transfer RNA
tRNA
title Structural basis for tRNA methylthiolation by the radical SAM enzyme MiaB
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