9kp4 | pdb_00009kp4
Crystal structure of human CASTOR1 in apo form
Structural highlights
FunctionMALE_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 PubMedMechanistic 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
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