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| | ==Crystal structure of human heteropentameric complex== | | ==Crystal structure of human heteropentameric complex== |
| - | <StructureSection load='5x6u' size='340' side='right' caption='[[5x6u]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='5x6u' size='340' side='right'caption='[[5x6u]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5x6u]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X6U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5X6U FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5x6u]] is a 5 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=5X6U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X6U FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5x6v|5x6v]]</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]] 2.4Å</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=5x6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x6u OCA], [http://pdbe.org/5x6u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5x6u RCSB], [http://www.ebi.ac.uk/pdbsum/5x6u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5x6u ProSAT]</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=5x6u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x6u OCA], [https://pdbe.org/5x6u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x6u RCSB], [https://www.ebi.ac.uk/pdbsum/5x6u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x6u ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/LTOR2_HUMAN LTOR2_HUMAN]] Primary immunodeficiency syndrome due to p14 deficiency. The disease is caused by mutations affecting the gene represented in this entry. | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LTOR4_HUMAN LTOR4_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated.<ref>PMID:22980980</ref> [[http://www.uniprot.org/uniprot/LTOR3_HUMAN LTOR3_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.<ref>PMID:20381137</ref> <ref>PMID:22980980</ref> [[http://www.uniprot.org/uniprot/LTOR5_HUMAN LTOR5_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.<ref>PMID:12773388</ref> <ref>PMID:22980980</ref> [[http://www.uniprot.org/uniprot/LTOR2_HUMAN LTOR2_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.<ref>PMID:20381137</ref> <ref>PMID:22980980</ref> [[http://www.uniprot.org/uniprot/LTOR1_HUMAN LTOR1_HUMAN]] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation.<ref>PMID:19654316</ref> <ref>PMID:20381137</ref> <ref>PMID:20544018</ref> <ref>PMID:22980980</ref> | + | [https://www.uniprot.org/uniprot/LTOR3_HUMAN LTOR3_HUMAN] As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.<ref>PMID:20381137</ref> <ref>PMID:22980980</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5x6u" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5x6u" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ragulator complex 3D structures|Ragulator complex 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Kitamura, A]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Li, S]] | + | [[Category: Large Structures]] |
| - | [[Category: Nada, S]] | + | [[Category: Kitamura A]] |
| - | [[Category: Nakagawa, A]] | + | [[Category: Li S]] |
| - | [[Category: Nakai, M]] | + | [[Category: Nada S]] |
| - | [[Category: Nakai, T]] | + | [[Category: Nakagawa A]] |
| - | [[Category: Nakatsumi, H]] | + | [[Category: Nakai M]] |
| - | [[Category: Nakayama, K I]] | + | [[Category: Nakai T]] |
| - | [[Category: Ogawa, A]] | + | [[Category: Nakatsumi H]] |
| - | [[Category: Okada, M]] | + | [[Category: Nakayama KI]] |
| - | [[Category: Standley, D M]] | + | [[Category: Ogawa A]] |
| - | [[Category: Yamashita, E]] | + | [[Category: Okada M]] |
| - | [[Category: Yonehara, R]] | + | [[Category: Standley DM]] |
| - | [[Category: Cell growth]]
| + | [[Category: Yamashita E]] |
| - | [[Category: Lysosome]]
| + | [[Category: Yonehara R]] |
| - | [[Category: Mtor signaling]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Ragulator complex]]
| + | |
| - | [[Category: Roadblock]]
| + | |
| - | [[Category: Scaffold]]
| + | |
| Structural highlights
Function
LTOR3_HUMAN As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.[1] [2]
Publication Abstract from PubMed
The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes.
Structural basis for the assembly of the Ragulator-Rag GTPase complex.,Yonehara R, Nada S, Nakai T, Nakai M, Kitamura A, Ogawa A, Nakatsumi H, Nakayama KI, Li S, Standley DM, Yamashita E, Nakagawa A, Okada M Nat Commun. 2017 Nov 20;8(1):1625. doi: 10.1038/s41467-017-01762-3. PMID:29158492[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010 Apr 16;141(2):290-303. doi: 10.1016/j.cell.2010.02.024. Epub 2010 Apr , 8. PMID:20381137 doi:10.1016/j.cell.2010.02.024
- ↑ Bar-Peled L, Schweitzer LD, Zoncu R, Sabatini DM. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell. 2012 Sep 14;150(6):1196-208. doi: 10.1016/j.cell.2012.07.032. PMID:22980980 doi:10.1016/j.cell.2012.07.032
- ↑ Yonehara R, Nada S, Nakai T, Nakai M, Kitamura A, Ogawa A, Nakatsumi H, Nakayama KI, Li S, Standley DM, Yamashita E, Nakagawa A, Okada M. Structural basis for the assembly of the Ragulator-Rag GTPase complex. Nat Commun. 2017 Nov 20;8(1):1625. doi: 10.1038/s41467-017-01762-3. PMID:29158492 doi:http://dx.doi.org/10.1038/s41467-017-01762-3
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