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5gv2

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Revision as of 11:43, 2 August 2023

Crystal structure of Arginine-bound CASTOR1 from Homo sapiens

Structural highlights

5gv2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.06Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The mTOR complex I (mTORC1) signaling pathway controls many metabolic processes and is regulated by amino acid signals, especially arginine. CASTOR1 has been identified as the cytosolic arginine sensor for the mTORC1 pathway, but the molecular mechanism of how it senses arginine is elusive. Here, by determining the crystal structure of human CASTOR1 in complex with arginine, we found that an exquisitely tailored pocket, carved between the NTD and the CTD domains of CASTOR1, is employed to recognize arginine. Mutation of critical residues in this pocket abolished or diminished arginine binding. By comparison with structurally similar aspartate kinases, a surface patch of CASTOR1-NTD on the opposite side of the arginine-binding site was identified to mediate direct physical interaction with its downstream effector GATOR2, via GATOR2 subunit Mios. Mutation of this surface patch disrupted CASTOR1's recognition and inhibition of GATOR2, revealed by in vitro pull-down assay. Normal mode (NM) analysis revealed an 'open'-to-'closed' conformational change for CASTOR1, which is correlated to the switching between the exposing and concealing of its GATOR2-binding residues, and is most likely related to arginine binding. Interestingly, the GATOR2-binding sites on the two protomers of CASTOR1 dimer face the same direction, which prompted us to propose a model for how dimerization of CASTOR1 relieves the inhibition of GATOR1 by GATOR2. Our study thus provides a thorough analysis on how CASTOR1 recognizes arginine, and describes a possible mechanism of how arginine binding induces the inter-domain movement of CASTOR1 to affect its association with GATOR2.

Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway.,Gai Z, Wang Q, Yang C, Wang L, Deng W, Wu G Cell Discov. 2016 Dec 27;2:16051. doi: 10.1038/celldisc.2016.51. eCollection, 2016. PMID:28066558^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Gai Z, Wang Q, Yang C, Wang L, Deng W, Wu G. Structural mechanism for the arginine sensing and regulation of CASTOR1 in the mTORC1 signaling pathway. Cell Discov. 2016 Dec 27;2:16051. doi: 10.1038/celldisc.2016.51. eCollection, 2016. PMID:28066558 doi:http://dx.doi.org/10.1038/celldisc.2016.51

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5gv2"

Categories: Homo sapiens | Large Structures | Gai ZC | Wu G

@@ Line 3: / Line 3: @@
 <StructureSection load='5gv2' size='340' side='right'caption='[[5gv2]], [[Resolution|resolution]] 2.06&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5gv2]] is a 2 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=5GV2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5GV2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5gv2]] is a 2 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=5GV2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5GV2 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=MG:MAGNESIUM+ION'>MG</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]] 2.06&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARG:ARGININE'>ARG</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5gv2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gv2 OCA], [http://pdbe.org/5gv2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5gv2 RCSB], [http://www.ebi.ac.uk/pdbsum/5gv2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5gv2 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=5gv2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5gv2 OCA], [https://pdbe.org/5gv2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5gv2 RCSB], [https://www.ebi.ac.uk/pdbsum/5gv2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5gv2 ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Gai, Z C]]
+[[Category: Gai ZC]]
-[[Category: Wu, G]]
+[[Category: Wu G]]
-[[Category: Arginine]]
-[[Category: Castor1]]
-[[Category: Dimer]]
-[[Category: Signaling protein]]

5gv2

From Proteopedia

Revision as of 11:43, 2 August 2023

Crystal structure of Arginine-bound CASTOR1 from Homo sapiens

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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