Structural insights into the RNA methyltransferase domain of METTL16

Abstract N 6-methyladenosine (m6A) is an abundant modification in messenger RNA and noncoding RNAs that affects RNA metabolism. Methyltransferase-like protein 16 (METTL16) is a recently confirmed m6A RNA methyltransferase that methylates U6 spliceosomal RNA and interacts with the 3′-terminal RNA tri...

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Autores principales:	Agnieszka Ruszkowska, Milosz Ruszkowski, Zbigniew Dauter, Jessica A. Brown
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c432554ac8cf4b92918adc32a9762164
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spelling	oai:doaj.org-article:c432554ac8cf4b92918adc32a97621642021-12-02T15:08:48ZStructural insights into the RNA methyltransferase domain of METTL1610.1038/s41598-018-23608-82045-2322https://doaj.org/article/c432554ac8cf4b92918adc32a97621642018-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-23608-8https://doaj.org/toc/2045-2322Abstract N 6-methyladenosine (m6A) is an abundant modification in messenger RNA and noncoding RNAs that affects RNA metabolism. Methyltransferase-like protein 16 (METTL16) is a recently confirmed m6A RNA methyltransferase that methylates U6 spliceosomal RNA and interacts with the 3′-terminal RNA triple helix of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1). Here, we present two X-ray crystal structures of the N-terminal methyltransferase domain (residues 1–291) of human METTL16 (METTL16_291): an apo structure at 1.9 Å resolution and a post-catalytic S-adenosylhomocysteine-bound complex at 2.1 Å resolution. The structures revealed a highly conserved Rossmann fold that is characteristic of Class I S-adenosylmethionine-dependent methyltransferases and a large, positively charged groove. This groove likely represents the RNA-binding site and it includes structural elements unique to METTL16. In-depth analysis of the active site led to a model of the methyl transfer reaction catalyzed by METTL16. In contrast to the major m6A methyltransferase heterodimer METTL3/METTL14, full-length METTL16 forms a homodimer and METTL16_291 exists as a monomer based on size-exclusion chromatography. A native gel-shift assay shows that METTL16 binds to the MALAT1 RNA triple helix, but monomeric METTL16_291 does not. Our results provide insights into the molecular structure of METTL16, which is distinct from METTL3/METTL14.Agnieszka RuszkowskaMilosz RuszkowskiZbigniew DauterJessica A. BrownNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Agnieszka Ruszkowska Milosz Ruszkowski Zbigniew Dauter Jessica A. Brown Structural insights into the RNA methyltransferase domain of METTL16
description	Abstract N 6-methyladenosine (m6A) is an abundant modification in messenger RNA and noncoding RNAs that affects RNA metabolism. Methyltransferase-like protein 16 (METTL16) is a recently confirmed m6A RNA methyltransferase that methylates U6 spliceosomal RNA and interacts with the 3′-terminal RNA triple helix of MALAT1 (metastasis-associated lung adenocarcinoma transcript 1). Here, we present two X-ray crystal structures of the N-terminal methyltransferase domain (residues 1–291) of human METTL16 (METTL16_291): an apo structure at 1.9 Å resolution and a post-catalytic S-adenosylhomocysteine-bound complex at 2.1 Å resolution. The structures revealed a highly conserved Rossmann fold that is characteristic of Class I S-adenosylmethionine-dependent methyltransferases and a large, positively charged groove. This groove likely represents the RNA-binding site and it includes structural elements unique to METTL16. In-depth analysis of the active site led to a model of the methyl transfer reaction catalyzed by METTL16. In contrast to the major m6A methyltransferase heterodimer METTL3/METTL14, full-length METTL16 forms a homodimer and METTL16_291 exists as a monomer based on size-exclusion chromatography. A native gel-shift assay shows that METTL16 binds to the MALAT1 RNA triple helix, but monomeric METTL16_291 does not. Our results provide insights into the molecular structure of METTL16, which is distinct from METTL3/METTL14.
format	article
author	Agnieszka Ruszkowska Milosz Ruszkowski Zbigniew Dauter Jessica A. Brown
author_facet	Agnieszka Ruszkowska Milosz Ruszkowski Zbigniew Dauter Jessica A. Brown
author_sort	Agnieszka Ruszkowska
title	Structural insights into the RNA methyltransferase domain of METTL16
title_short	Structural insights into the RNA methyltransferase domain of METTL16
title_full	Structural insights into the RNA methyltransferase domain of METTL16
title_fullStr	Structural insights into the RNA methyltransferase domain of METTL16
title_full_unstemmed	Structural insights into the RNA methyltransferase domain of METTL16
title_sort	structural insights into the rna methyltransferase domain of mettl16
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/c432554ac8cf4b92918adc32a9762164
work_keys_str_mv	AT agnieszkaruszkowska structuralinsightsintothernamethyltransferasedomainofmettl16 AT miloszruszkowski structuralinsightsintothernamethyltransferasedomainofmettl16 AT zbigniewdauter structuralinsightsintothernamethyltransferasedomainofmettl16 AT jessicaabrown structuralinsightsintothernamethyltransferasedomainofmettl16
_version_	1718388025537331200

Structural insights into the RNA methyltransferase domain of METTL16

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