Evidence map›Paper›PMID 27422871›Full record

ArticleNucleic acids research2016

Molecular basis of RNA guanine-7 methyltransferase (RNMT) activation by RAM.

Dhaval Varshney, Alain-Pierre Petit, Juan A Bueren-Calabuig, Chimed Jansen, Dan A Fletcher, Mark Peggie, Simone Weidlich, Paul Scullion, Andrei V Pisliakov, Victoria H Cowling

Abstract read
In one paragraph

Article in Nucleic acids research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.

0numbers the graph read from it
0cells of the map it votes in
52citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

52 citing papers in PubMed.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors.

Dhaval VarshneyCentre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Alain-Pierre PetitDrug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Juan A Bueren-CalabuigComputational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Chimed JansenDrug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Dan A FletcherDrug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Mark PeggieDivision of Signal Transduction Therapies, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Simone WeidlichDivision of Signal Transduction Therapies, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Paul ScullionDrug Discovery Unit, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Andrei V PisliakovComputational Biology, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Victoria H CowlingCentre for Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK v.h.cowling@dundee.ac.uk.

Funding

Medical Research Council G0700240Medical Research Council MC_PC_12013Medical Research Council MC_PC_13061Medical Research Council MR/K024213/1
6 · The paper itself

Abstract

Maturation and translation of mRNA in eukaryotes requires the addition of the 7-methylguanosine cap. In vertebrates, the cap methyltransferase, RNA guanine-7 methyltransferase (RNMT), has an activating subunit, RNMT-Activating Miniprotein (RAM). Here we report the first crystal structure of the human RNMT in complex with the activation domain of RAM. A relatively unstructured and negatively charged RAM binds to a positively charged surface groove on RNMT, distal to the active site. This results in stabilisation of a RNMT lobe structure which co-evolved with RAM and is required for RAM binding. Structure-guided mutagenesis and molecular dynamics simulations reveal that RAM stabilises the structure and positioning of the RNMT lobe and the adjacent α-helix hinge, resulting in optimal positioning of helix A which contacts substrates in the active site. Using biophysical and biochemical approaches, we observe that RAM increases the recruitment of the methyl donor, AdoMet (S-adenosyl methionine), to RNMT. Thus we report the mechanism by which RAM allosterically activates RNMT, allowing it to function as a molecular rheostat for mRNA cap methylation.

Indexed as

Amino Acid SequenceAmino Acid SubstitutionBinding SitesCatalysisCatalytic DomainEnzyme ActivationHumansMagnetic Resonance SpectroscopyMethyltransferasesModels, MolecularMutationProtein BindingProtein ConformationProtein Interaction Domains and MotifsProtein StabilityRNA-Binding ProteinsMethyltransferasesmRNA (guanine(N7))-methyltransferaseRAMAC protein, humanRNA-Binding Proteins

Identifiers

PMID27422871
PMCPMC5137418

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.