View source for 7ux2


==cryo-EM structure of the Raptor-TFEB-Rag-Ragulator complex==
<StructureSection load='7ux2' size='340' side='right'caption='[[7ux2]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ux2]] is a 16 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=7UX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7UX2 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]] 2.9&#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=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=7ux2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ux2 OCA], [https://pdbe.org/7ux2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ux2 RCSB], [https://www.ebi.ac.uk/pdbsum/7ux2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ux2 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RPTOR_HUMAN RPTOR_HUMAN] Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis.<ref>PMID:12150925</ref> <ref>PMID:12150926</ref> <ref>PMID:23727834</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 7ux2" 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]]