8d9k: Difference between revisions

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'''Unreleased structure'''


The entry 8d9k is ON HOLD
==CryoEM structure of human METTL1-WDR4 in complex with Lys-tRNA==
<StructureSection load='8d9k' size='340' side='right'caption='[[8d9k]], [[Resolution|resolution]] 3.72&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8d9k]] 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=8D9K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8D9K FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.72&#8491;</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=8d9k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8d9k OCA], [https://pdbe.org/8d9k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8d9k RCSB], [https://www.ebi.ac.uk/pdbsum/8d9k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8d9k 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 the METTL1-WDR4 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:31031083, PubMed:31031084, PubMed:36599982, PubMed:36599985, PubMed:37369656). In the METTL1-WDR4 methyltransferase complex, WDR4 acts as a scaffold for tRNA-binding (PubMed:36599982, PubMed:36599985, PubMed:37369656). Required for the formation of N(7)-methylguanine at position 46 (m7G46) in a large subset of tRNAs that contain the 5'-RAGGU-3' motif within the variable loop (PubMed:12403464, PubMed:34352206, PubMed:34352207, PubMed:36599982, PubMed:36599985, PubMed:37369656). M7G46 interacts with C13-G22 in the D-loop to stabilize tRNA tertiary structure and protect tRNAs from decay (PubMed:36599982, PubMed:36599985). Also required for the formation of N(7)-methylguanine at internal sites in a subset of mRNAs (PubMed:31031084, PubMed:37379838). 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> <ref>PMID:34352206</ref> <ref>PMID:34352207</ref> <ref>PMID:36599982</ref> <ref>PMID:36599985</ref> <ref>PMID:37369656</ref> <ref>PMID:37379838</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.


Authors:  
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;613(7943):383-390. doi: 10.1038/s41586-022-05565-5. Epub 2023 , Jan 4. PMID:36599982<ref>PMID:36599982</ref>


Description:  
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 8d9k" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Nam Y]]
[[Category: Ruiz-Arroyo VM]]
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