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| | <StructureSection load='5gt7' size='340' side='right'caption='[[5gt7]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='5gt7' size='340' side='right'caption='[[5gt7]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5gt7]] is a 4 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=5GT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GT7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5gt7]] is a 4 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=5GT7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GT7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ARG:ARGININE'>ARG</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></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]] 2.048Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5gt8|5gt8]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARG:ARGININE'>ARG</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GATSL3, CASTOR1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5gt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gt7 OCA], [https://pdbe.org/5gt7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gt7 RCSB], [https://www.ebi.ac.uk/pdbsum/5gt7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gt7 ProSAT]</span></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=5gt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gt7 OCA], [http://pdbe.org/5gt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5gt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gt7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GATL3_HUMAN GATL3_HUMAN]] Functions as an intracellular arginine sensor that regulates the TORC1 signaling pathway through the GATOR complex. As a homooligomer or a heterooligomer with GATSL2, directly binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of arginine to GATSL3 disrupts the interaction of GATSL3-containing oligomers with GATOR2 and activates the TORC1 signaling pathway.<ref>PMID:26972053</ref> | + | [https://www.uniprot.org/uniprot/CAST1_HUMAN CAST1_HUMAN] Functions as an intracellular arginine sensor within the amino acid-sensing branch of the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058). As a homodimer or a heterodimer with CASTOR2, binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1 (PubMed:26972053, PubMed:27487210, PubMed:33594058). Binding of arginine to CASTOR1 allosterically disrupts the interaction of CASTOR1-containing dimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058).<ref>PMID:26972053</ref> <ref>PMID:27487210</ref> <ref>PMID:33594058</ref> |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of metabolism and cell growth. Among the numerous extracellular and intracellular signals, certain amino acids activate mTORC1 in a Rag-dependent manner. Arginine can stimulate mTORC1 activity by releasing the inhibitor CASTOR1 (Cellular Arginine Sensor of mTORC1) from GATOR2, a positive regulator of mTORC1 which interacts with GATOR1, the GAP for RagA/B. Three groups have resolved the structures of arginine-CASTOR1 complex, shedding a new light on molecular basis of the regulation of mTORC1 activity by arginine. However, lacking the apo structure of CASTOR1 prelimited the molecular understanding of mechanism underlying mTORC1 regulation. Here, we report crystal structures of arginine sensor CASTOR1 in arginine-bound and ligand free states at 2.05A and 2.8A, respectively. Structural comparison of CASTOR1 between two states reveals near identical conformations, except in two loop regions. It indicates CASTOR1 does not undergo large conformational change during arginine binding. Therefore, we conclude a detailed structural interpretation of arginine sensing by CASTOR1 in mTORC1 pathway.
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| - | Crystal structures of arginine sensor CASTOR1 in arginine-bound and ligand free states.,Zhou Y, Wang C, Xiao Q, Guo L Biochem Biophys Res Commun. 2019 Jan 8;508(2):387-391. doi:, 10.1016/j.bbrc.2018.11.147. Epub 2018 Nov 28. PMID:30503338<ref>PMID:30503338</ref>
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 5gt7" style="background-color:#fffaf0;"></div>
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| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Deng, D]] | + | [[Category: Deng D]] |
| - | [[Category: Guo, L]] | + | [[Category: Guo L]] |
| - | [[Category: Act domain]]
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| - | [[Category: Arginine binding]]
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| - | [[Category: Castor1]]
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| - | [[Category: Gator2]]
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| - | [[Category: Gatsl2]]
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| - | [[Category: Mtor]]
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| - | [[Category: Signaling protein]]
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| Structural highlights
Function
CAST1_HUMAN Functions as an intracellular arginine sensor within the amino acid-sensing branch of the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058). As a homodimer or a heterodimer with CASTOR2, binds and inhibits the GATOR subcomplex GATOR2 and thereby mTORC1 (PubMed:26972053, PubMed:27487210, PubMed:33594058). Binding of arginine to CASTOR1 allosterically disrupts the interaction of CASTOR1-containing dimers with GATOR2 which can in turn activate mTORC1 and the TORC1 signaling pathway (PubMed:26972053, PubMed:27487210, PubMed:33594058).[1] [2] [3]
References
- ↑ Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, Wang T, Harper JW, Gygi SP, Sabatini DM. The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell. 2016 Mar 24;165(1):153-64. doi: 10.1016/j.cell.2016.02.035. Epub 2016 Mar, 10. PMID:26972053 doi:http://dx.doi.org/10.1016/j.cell.2016.02.035
- ↑ Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature. 2016 Aug 11;536(7615):229-33. PMID:27487210 doi:http://dx.doi.org/10.1038/nature19079
- ↑ Li T, Wang X, Ju E, da Silva SR, Chen L, Zhang X, Wei S, Gao SJ. RNF167 activates mTORC1 and promotes tumorigenesis by targeting CASTOR1 for ubiquitination and degradation. Nat Commun. 2021 Feb 16;12(1):1055. PMID:33594058 doi:10.1038/s41467-021-21206-3
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