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| | ==Crystal structure of the human METTL3-METTL14 complex bound to SAM== | | ==Crystal structure of the human METTL3-METTL14 complex bound to SAM== |
| - | <StructureSection load='5l6e' size='340' side='right' caption='[[5l6e]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='5l6e' size='340' side='right'caption='[[5l6e]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5l6e]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L6E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5L6E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5l6e]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5L6E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L6E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.901Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">METTL3, MTA70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), METTL14, KIAA1627 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/mRNA_(2'-O-methyladenosine-N(6)-)-methyltransferase mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.62 2.1.1.62] </span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5l6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l6e OCA], [https://pdbe.org/5l6e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l6e RCSB], [https://www.ebi.ac.uk/pdbsum/5l6e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l6e ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5l6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l6e OCA], [http://pdbe.org/5l6e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l6e RCSB], [http://www.ebi.ac.uk/pdbsum/5l6e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l6e ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN]] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref> [[http://www.uniprot.org/uniprot/MET14_HUMAN MET14_HUMAN]] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4]<ref>PMID:24316715</ref> <ref>PMID:24407421</ref> <ref>PMID:25719671</ref> | + | [https://www.uniprot.org/uniprot/MTA70_HUMAN MTA70_HUMAN] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]<ref>PMID:22575960</ref> <ref>PMID:24284625</ref> <ref>PMID:25719671</ref> <ref>PMID:25799998</ref> <ref>PMID:26321680</ref> <ref>PMID:26593424</ref> <ref>PMID:9409616</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Jinek, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Sledz, P]] | + | [[Category: Jinek M]] |
| - | [[Category: Methyltransferase n6-adenine methylation m6a rossmann fold]] | + | [[Category: Sledz P]] |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
MTA70_HUMAN N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7][1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
Methylation of adenosines at the N(6) position (m(6)A) is a dynamic and abundant epitranscriptomic mark that regulates critical aspects of eukaryotic RNA metabolism in numerous biological processes. The RNA methyltransferases METTL3 and METTL14 are components of a multisubunit m(6)A writer complex whose enzymatic activity is substantially higher than the activities of METTL3 or METTL14 alone. The molecular mechanism underpinning this synergistic effect is poorly understood. Here we report the crystal structure of the catalytic core of the human m(6)A writer complex comprising METTL3 and METTL14. The structure reveals the heterodimeric architecture of the complex and donor substrate binding by METTL3. Structure-guided mutagenesis indicates that METTL3 is the catalytic subunit of the complex, whereas METTL14 has a degenerate active site and plays non-catalytic roles in maintaining complex integrity and substrate RNA binding. These studies illuminate the molecular mechanism and evolutionary history of eukaryotic m(6)A modification in post-transcriptional genome regulation.
Structural insights into the molecular mechanism of the m(6)A writer complex.,Sledz P, Jinek M Elife. 2016 Sep 14;5. pii: e18434. doi: 10.7554/eLife.18434. PMID:27627798[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112. PMID:22575960 doi:http://dx.doi.org/10.1038/nature11112
- ↑ Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27. PMID:24284625 doi:http://dx.doi.org/10.1038/nature12730
- ↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
- ↑ Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015 Mar 26;519(7544):482-5. doi: 10.1038/nature14281. Epub 2015 Mar 18. PMID:25799998 doi:http://dx.doi.org/10.1038/nature14281
- ↑ Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015 Sep 10;162(6):1299-308. doi: 10.1016/j.cell.2015.08.011. Epub 2015 Aug, 27. PMID:26321680 doi:http://dx.doi.org/10.1016/j.cell.2015.08.011
- ↑ Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 5' UTR m(6)A Promotes Cap-Independent Translation. Cell. 2015 Nov 5;163(4):999-1010. doi: 10.1016/j.cell.2015.10.012. Epub 2015 Oct , 22. PMID:26593424 doi:http://dx.doi.org/10.1016/j.cell.2015.10.012
- ↑ Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997 Nov;3(11):1233-47. PMID:9409616
- ↑ Sledz P, Jinek M. Structural insights into the molecular mechanism of the m(6)A writer complex. Elife. 2016 Sep 14;5. pii: e18434. doi: 10.7554/eLife.18434. PMID:27627798 doi:http://dx.doi.org/10.7554/eLife.18434
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