|
|
| (5 intermediate revisions by the same user not shown) |
| Line 1: |
Line 1: |
|
| |
|
| ==Cryo-EM structure of GATOR1-RAG== | | ==Cryo-EM structure of GATOR1-RAG== |
| <StructureSection load='6ces' size='340' side='right' caption='[[6ces]], [[Resolution|resolution]] 4.00Å' scene=''> | | <SX load='6ces' size='340' side='right' viewer='molstar' caption='[[6ces]], [[Resolution|resolution]] 4.00Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6ces]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6CES OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6CES FirstGlance]. <br> | | <table><tr><td colspan='2'>[[6ces]] 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=6CES OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6CES FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene></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]] 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=6ces FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ces OCA], [http://pdbe.org/6ces PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ces RCSB], [http://www.ebi.ac.uk/pdbsum/6ces PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ces ProSAT]</span></td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</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=6ces FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ces OCA], [https://pdbe.org/6ces PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ces RCSB], [https://www.ebi.ac.uk/pdbsum/6ces PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ces 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/RRAGA_HUMAN RRAGA_HUMAN]] Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form. In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death. May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.<ref>PMID:20381137</ref> <ref>PMID:25936802</ref> <ref>PMID:8995684</ref> <ref>PMID:9394008</ref> [[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> [[http://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> | | [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> |
| | |
| | ==See Also== |
| | *[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </SX> |
| [[Category: Brignole, E J]] | | [[Category: Homo sapiens]] |
| [[Category: Huang, R K]] | | [[Category: Large Structures]] |
| [[Category: Sabatini, D M]] | | [[Category: Brignole EJ]] |
| [[Category: Shen, K]] | | [[Category: Huang RK]] |
| [[Category: Yu, Z]] | | [[Category: Sabatini DM]] |
| [[Category: Mtorc1 amino-acid sensing lysosome growth control]] | | [[Category: Shen K]] |
| [[Category: Signaling protein]] | | [[Category: Yu Z]] |