View source for 7uxh


==cryo-EM structure of the mTORC1-TFEB-Rag-Ragulator complex==
<StructureSection load='7uxh' size='340' side='right'caption='[[7uxh]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7uxh]] is a 34 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=7UXH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UXH 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]] 3.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GTP:GUANOSINE-5-TRIPHOSPHATE'>GTP</scene>, <scene name='pdbligand=IHP:INOSITOL+HEXAKISPHOSPHATE'>IHP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=7uxh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7uxh OCA], [https://pdbe.org/7uxh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7uxh RCSB], [https://www.ebi.ac.uk/pdbsum/7uxh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7uxh ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RRAGC_HUMAN RRAGC_HUMAN] Guanine nucleotide-binding protein forming heterodimeric Rag complexes required for the amino acid-induced relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the TOR signaling cascade by amino acids.<ref>PMID:20381137</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The transcription factor TFEB is a master regulator of lysosomal biogenesis and autophagy(1). The phosphorylation of TFEB by the mechanistic target of rapamycin complex 1 (mTORC1)(2-5) is unique in its mTORC1 substrate recruitment mechanism, which is strictly dependent on the amino acid-mediated activation of the RagC GTPase activating protein FLCN(6,7). TFEB lacks the TOR signalling motif responsible for the recruitment of other mTORC1 substrates. We used cryogenic-electron microscopy to determine the structure of TFEB as presented to mTORC1 for phosphorylation, which we refer to as the 'megacomplex'. Two full Rag-Ragulator complexes present each molecule of TFEB to the mTOR active site. One Rag-Ragulator complex is bound to Raptor in the canonical mode seen previously in the absence of TFEB. A second Rag-Ragulator complex (non-canonical) docks onto the first through a RagC GDP-dependent contact with the second Ragulator complex. The non-canonical Rag dimer binds the first helix of TFEB with a RagC(GDP)-dependent aspartate clamp in the cleft between the Rag G domains. In cellulo mutation of the clamp drives TFEB constitutively into the nucleus while having no effect on mTORC1 localization. The remainder of the 108-amino acid TFEB docking domain winds around Raptor and then back to RagA. The double use of RagC GDP contacts in both Rag dimers explains the strong dependence of TFEB phosphorylation on FLCN and the RagC GDP state.

Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex.,Cui Z, Napolitano G, de Araujo MEG, Esposito A, Monfregola J, Huber LA, Ballabio A, Hurley JH Nature. 2023 Feb;614(7948):572-579. doi: 10.1038/s41586-022-05652-7. Epub 2023 , Jan 25. PMID:36697823<ref>PMID:36697823</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7uxh" style="background-color:#fffaf0;"></div>

==See Also==
*[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]]
*[[Ragulator complex 3D structures|Ragulator complex 3D structures]]
*[[Raptor 3D structures|Raptor 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cui Z]]
[[Category: Hurley J]]