5gs9 | pdb_00005gs9
Crystal structure of CASTOR1-arginine
Structural highlights
FunctionCAST1_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 PubMedThe mechanistic Target Of Rapamycin Complex 1 (mTORC1) is central to the cellular response to changes in nutrient signals such as amino acids. CASTOR1 is shown to be an arginine sensor, which plays an important role in the activation of the mTORC1 pathway. In the deficiency of arginine, CASTOR1 interacts with GATOR2, which together with GATOR1 and Rag GTPases controls the relocalization of mTORC1 to lysosomes. The binding of arginine to CASTOR1 disrupts its association with GATOR2 and hence activates the mTORC1 signaling. Here, we report the crystal structure of CASTOR1 in complex with arginine at 2.5 A resolution. CASTOR1 comprises of four tandem ACT domains with an architecture resembling the C-terminal allosteric domains of aspartate kinases. ACT1 and ACT3 adopt the typical betaalphabetabetaalphabeta topology and function in dimerization via the conserved residues from helices alpha1 of ACT1 and alpha5 of ACT3; whereas ACT 2 and ACT4, both comprising of two non-sequential regions, assume the unusual betabetaalphabetabetaalpha topology and contribute an arginine-binding pocket at the interface. The bound arginine makes a number of hydrogen-bonding interactions and extensive hydrophobic contacts with the surrounding residues of the binding pocket. The functional roles of the key residues are validated by mutagenesis and biochemical assays. Our structural and functional data together reveal the molecular basis for the arginine-binding specificity of CASTOR1 in the arginine-dependent activation of the mTORC1 signaling. Structural insight into the arginine-binding specificity of CASTOR1 in amino acid-dependent mTORC1 signaling.,Xia J, Wang R, Zhang T, Ding J Cell Discov. 2016 Sep 13;2:16035. doi: 10.1038/celldisc.2016.35. eCollection, 2016. PMID:27648300[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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