9kp4: Difference between revisions

Latest revision as of 07:46, 25 March 2026

Crystal structure of human CASTOR1 in apo form

Structural highlights

9kp4 is a 4 chain structure with sequence from Escherichia coli K-12 and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.08Å
Ligands:	ACY, GLC, NH4, PRD_900001
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MALE_ECOLI Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.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

Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.

CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity.,Liu C, Zhang Y, Wang Y, Wu M, Li Y, Wei J, Shi J, Wang R, Su L, Yang T, Li J, Xiao J, Ding J, Zhang T Mol Cell. 2026 Jan 22;86(2):362-375.e4. doi: 10.1016/j.molcel.2025.12.016. Epub , 2026 Jan 7. PMID:41506264^[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:https://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:https://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
↑ Liu C, Zhang Y, Wang Y, Wu M, Li Y, Wei J, Shi J, Wang R, Su L, Yang T, Li J, Xiao J, Ding J, Zhang T. CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity. Mol Cell. 2026 Jan 22;86(2):362-375.e4. PMID:41506264 doi:10.1016/j.molcel.2025.12.016

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OCA

[1] 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:https://dx.doi.org/10.1016/j.cell.2016.02.035

[2] 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:https://dx.doi.org/10.1038/nature19079

[3] 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

[4] Liu C, Zhang Y, Wang Y, Wu M, Li Y, Wei J, Shi J, Wang R, Su L, Yang T, Li J, Xiao J, Ding J, Zhang T. CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity. Mol Cell. 2026 Jan 22;86(2):362-375.e4. PMID:41506264 doi:10.1016/j.molcel.2025.12.016

[1]

[2]

[3]

[4]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9kp4 is ON HOLD  until Paper Publication
+==Crystal structure of human CASTOR1 in apo form==
+<StructureSection load='9kp4' size='340' side='right'caption='[[9kp4]], [[Resolution|resolution]] 3.08&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9kp4]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9KP4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9KP4 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.08&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=NH4:AMMONIUM+ION'>NH4</scene>, <scene name='pdbligand=PRD_900001:alpha-maltose'>PRD_900001</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=9kp4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9kp4 OCA], [https://pdbe.org/9kp4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9kp4 RCSB], [https://www.ebi.ac.uk/pdbsum/9kp4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9kp4 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/MALE_ECOLI MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides.[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 ==
+Mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of cell growth, responding to amino acid availability. While mTORC1 is modulated by amino acid sensors like CASTOR1, the mechanisms driving its dynamic response to fluctuating amino acid levels remain unclear. Here, we investigate the role of CASTOR2, an understudied CASTOR1 homolog, in regulating mTORC1 activity. We show that CASTOR1 and CASTOR2 bind to arginine similarly but differ in their sensitivity: CASTOR1 responds to low arginine levels, whereas CASTOR2 responds to high arginine concentrations. Both proteins interact with the GATOR2 component Mios, inhibiting its binding to GATOR1. Arginine binding to CASTOR1/2 induces conformational changes at the aspartate kinase, chorismate mutase, and TyrA (ACT) domain (ACT2-ACT4) interface, leading to its dissociation from Mios. Functionally, we demonstrate that CASTOR proteins are highly expressed in muscle tissue and, in C2C12 cells, they regulate mTORC1 and myogenesis in response to different arginine availability. These findings highlight how CASTOR proteins function as dual arginine sensors to fine-tune mTORC1 activity.
-Authors: Liu, C., Ding, J., Zhang, T.
+CASTOR1 and CASTOR2 respond to different arginine levels to regulate mTORC1 activity.,Liu C, Zhang Y, Wang Y, Wu M, Li Y, Wei J, Shi J, Wang R, Su L, Yang T, Li J, Xiao J, Ding J, Zhang T Mol Cell. 2026 Jan 22;86(2):362-375.e4. doi: 10.1016/j.molcel.2025.12.016. Epub , 2026 Jan 7. PMID:41506264<ref>PMID:41506264</ref>
-Description: Crystal structure of human CASTOR1 in apo form
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Zhang, T]]
+<div class="pdbe-citations 9kp4" style="background-color:#fffaf0;"></div>
-[[Category: Liu, C]]
+== References ==
-[[Category: Ding, J]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Escherichia coli K-12]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Ding J]]
+[[Category: Liu C]]
+[[Category: Zhang T]]

9kp4: Difference between revisions

Latest revision as of 07:46, 25 March 2026

Crystal structure of human CASTOR1 in apo form

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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