8d9l
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | The entry | + | ==CryoEM structure of human METTL1-WDR4 in complex with Lys-tRNA and SAM== |
| + | <StructureSection load='8d9l' size='340' side='right'caption='[[8d9l]], [[Resolution|resolution]] 4.04Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8d9l]] is a 3 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=8D9L OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8D9L FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></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=8d9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8d9l OCA], [https://pdbe.org/8d9l PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8d9l RCSB], [https://www.ebi.ac.uk/pdbsum/8d9l PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8d9l ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/WDR4_HUMAN WDR4_HUMAN] Galloway-Mowat syndrome. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/WDR4_HUMAN WDR4_HUMAN] Non-catalytic component of a methyltransferase complex required for the formation of N(7)-methylguanine in a subset of RNA species, such as tRNAs, mRNAs and microRNAs (miRNAs) (PubMed:12403464, PubMed:31031084, PubMed:31031083). In the methyltransferase complex, it is required to stabilize and induce conformational changes of the catalytic subunit (PubMed:12403464). Required for the formation of N(7)-methylguanine at position 46 (m7G46) in tRNA (PubMed:12403464, PubMed:31031084). Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084). Also required for methylation of a specific subset of miRNAs, such as let-7 (PubMed:31031083). Independently of METTL1, also plays a role in genome stability: localizes at the DNA replication site and regulates endonucleolytic activities of FEN1 (PubMed:26751069).<ref>PMID:12403464</ref> <ref>PMID:26751069</ref> <ref>PMID:31031083</ref> <ref>PMID:31031084</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Specific, regulated modification of RNAs is important for proper gene expression(1,2). tRNAs are rich with various chemical modifications that affect their stability and function(3,4). 7-Methylguanosine (m(7)G) at tRNA position 46 is a conserved modification that modulates steady-state tRNA levels to affect cell growth(5,6). The METTL1-WDR4 complex generates m(7)G46 in humans, and dysregulation of METTL1-WDR4 has been linked to brain malformation and multiple cancers(7-22). Here we show how METTL1 and WDR4 cooperate to recognize RNA substrates and catalyse methylation. A crystal structure of METTL1-WDR4 and cryo-electron microscopy structures of METTL1-WDR4-tRNA show that the composite protein surface recognizes the tRNA elbow through shape complementarity. The cryo-electron microscopy structures of METTL1-WDR4-tRNA with S-adenosylmethionine or S-adenosylhomocysteine along with METTL1 crystal structures provide additional insights into the catalytic mechanism by revealing the active site in multiple states. The METTL1 N terminus couples cofactor binding with conformational changes in the tRNA, the catalytic loop and the WDR4 C terminus, acting as the switch to activate m(7)G methylation. Thus, our structural models explain how post-translational modifications of the METTL1 N terminus can regulate methylation. Together, our work elucidates the core and regulatory mechanisms underlying m(7)G modification by METTL1, providing the framework to understand its contribution to biology and disease. | ||
| - | + | Structures and mechanisms of tRNA methylation by METTL1-WDR4.,Ruiz-Arroyo VM, Raj R, Babu K, Onolbaatar O, Roberts PH, Nam Y Nature. 2023 Jan 4. doi: 10.1038/s41586-022-05565-5. PMID:36599982<ref>PMID:36599982</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8d9l" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Nam Y]] | ||
| + | [[Category: Ruiz-Arroyo VM]] | ||
Revision as of 07:41, 11 January 2023
CryoEM structure of human METTL1-WDR4 in complex with Lys-tRNA and SAM
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