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| | <SX load='6cet' size='340' side='right' viewer='molstar' caption='[[6cet]], [[Resolution|resolution]] 4.40Å' scene=''> | | <SX load='6cet' size='340' side='right' viewer='molstar' caption='[[6cet]], [[Resolution|resolution]] 4.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6cet]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CET OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6CET FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6cet]] 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=6CET OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CET FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NPRL2, TUSC4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), NPRL3, C16orf35, CGTHBA, MARE ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DEPDC5, KIAA0645 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.4Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6cet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cet OCA], [http://pdbe.org/6cet PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6cet RCSB], [http://www.ebi.ac.uk/pdbsum/6cet PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6cet 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=6cet FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6cet OCA], [https://pdbe.org/6cet PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6cet RCSB], [https://www.ebi.ac.uk/pdbsum/6cet PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6cet ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/NPRL2_HUMAN NPRL2_HUMAN]] Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).<ref>PMID:23723238</ref> The disease is caused by mutations affecting the gene represented in this entry. [[http://www.uniprot.org/uniprot/DEPD5_HUMAN DEPD5_HUMAN]] Rolandic epilepsy;Autosomal dominant nocturnal frontal lobe epilepsy;Autosomal dominant epilepsy with auditory features;Familial focal epilepsy with variable foci. The disease is caused by mutations affecting the gene represented in this entry. Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including DEPDC5, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).<ref>PMID:23723238</ref> [[http://www.uniprot.org/uniprot/NPRL3_HUMAN NPRL3_HUMAN]] Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).<ref>PMID:23723238</ref> The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/NPRL2_HUMAN NPRL2_HUMAN] Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).<ref>PMID:23723238</ref> The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NPRL2_HUMAN NPRL2_HUMAN]] As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.<ref>PMID:23723238</ref> Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs.<ref>PMID:18616680</ref> [[http://www.uniprot.org/uniprot/DEPD5_HUMAN DEPD5_HUMAN]] As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.<ref>PMID:23723238</ref> <ref>PMID:25457612</ref> [[http://www.uniprot.org/uniprot/NPRL3_HUMAN NPRL3_HUMAN]] As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.<ref>PMID:23723238</ref> | + | [https://www.uniprot.org/uniprot/NPRL2_HUMAN NPRL2_HUMAN] As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.<ref>PMID:23723238</ref> Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs.<ref>PMID:18616680</ref> |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
| + | |
| - | Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes. GATOR1 adopts an extended architecture with a cavity in the middle; NPRL2 links DEPDC5 and NPRL3, and DEPDC5 contacts the Rag GTPase heterodimer. Biochemical analyses reveal that our GATOR1-Rag GTPases structure is inhibitory, and that at least two binding modes must exist between the Rag GTPases and GATOR1. Direct interaction of DEPDC5 with RAGA inhibits GATOR1-mediated stimulation of GTP hydrolysis by RAGA, whereas weaker interactions between the NPRL2-NPRL3 heterodimer and RAGA execute GAP activity. These data reveal the structure of a component of the nutrient-sensing mTORC1 pathway and a non-canonical interaction between a GAP and its substrate GTPase.
| + | |
| - | | + | |
| - | Architecture of the human GATOR1 and GATOR1-Rag GTPases complexes.,Shen K, Huang RK, Brignole EJ, Condon KJ, Valenstein ML, Chantranupong L, Bomaliyamu A, Choe A, Hong C, Yu Z, Sabatini DM Nature. 2018 Apr 5;556(7699):64-69. doi: 10.1038/nature26158. Epub 2018 Mar 28. PMID:29590090<ref>PMID:29590090</ref>
| + | |
| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| + | |
| - | </div>
| + | |
| - | <div class="pdbe-citations 6cet" style="background-color:#fffaf0;"></div>
| + | |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </SX> | | </SX> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brignole, E J]] | + | [[Category: Brignole EJ]] |
| - | [[Category: Huang, R K]] | + | [[Category: Huang RK]] |
| - | [[Category: Sabatini, D M]] | + | [[Category: Sabatini DM]] |
| - | [[Category: Shen, K]] | + | [[Category: Shen K]] |
| - | [[Category: Yu, Z]] | + | [[Category: Yu Z]] |
| - | [[Category: Mtorc1 amino-acid sensing lysosome growth control]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| Structural highlights
Disease
NPRL2_HUMAN Inactivating mutations and truncating deletions in the genes encoding GATOR1 proteins, including NPRL2, are detected in glioblastoma and ovarian tumors and are associated with loss of heterozygosity events. Inactivation of GATOR1 proteins promotes constitutive localization of mTORC1 to the lysosomal membrane and blocks mTORC1 inactivation following amino acid withdrawal (PubMed:23723238).[1] The disease is caused by mutations affecting the gene represented in this entry.
Function
NPRL2_HUMAN As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway. The GATOR1 complex strongly increases GTP hydrolysis by RRAGA and RRAGB within RRAGC-containing heterodimers, thereby deactivating RRAGs, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. The GATOR1 complex is negatively regulated by GATOR2 the other GATOR subcomplex in this amino acid-sensing branch of the TORC1 pathway.[2] Suppresses Src-dependent tyrosine phosphorylation and activation of PDPK1 and its downstream signaling. Down-regulates PDPK1 kinase activity by interfering with tyrosine phosphorylation at 'Tyr-9', 'Tyr-373' and 'Tyr-376' residues. May act as a tumor suppressor. Suppresses cell growth and enhances sensitivity to various anticancer drugs.[3]
References
- ↑ Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044. PMID:23723238 doi:http://dx.doi.org/10.1126/science.1232044
- ↑ Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013 May 31;340(6136):1100-6. doi: 10.1126/science.1232044. PMID:23723238 doi:http://dx.doi.org/10.1126/science.1232044
- ↑ Kurata A, Katayama R, Watanabe T, Tsuruo T, Fujita N. TUSC4/NPRL2, a novel PDK1-interacting protein, inhibits PDK1 tyrosine phosphorylation and its downstream signaling. Cancer Sci. 2008 Sep;99(9):1827-34. Epub 2008 Jul 4. PMID:18616680 doi:http://dx.doi.org/CAS874
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