| 2016 |
Crystal structure of arginine-bound CASTOR1 at 1.8 Å resolution reveals that homodimeric CASTOR1 binds arginine at the interface of two ACT domains, enabling allosteric control of the adjacent GATOR2-binding site; arginine binding triggers dissociation from GATOR2, thereby activating mTORC1 downstream. |
X-ray crystallography (1.8 Å), structure-guided mutagenesis, biochemical binding assays |
Nature |
High |
27487210
|
| 2016 |
Crystal structure of human CASTOR1–arginine complex identifies an arginine-binding pocket between the NTD and CTD (ACT) domains; a surface patch on CASTOR1-NTD opposite this pocket mediates direct physical interaction with GATOR2 subunit Mios; mutation of key pocket residues abolishes or diminishes arginine binding, and mutation of the surface patch disrupts CASTOR1 recognition and inhibition of GATOR2. |
X-ray crystallography, in vitro pull-down assay, site-directed mutagenesis, normal mode analysis |
Cell discovery |
High |
28066558
|
| 2016 |
Crystal structure of CASTOR1–arginine complex at 2.5 Å shows four tandem ACT domains; ACT1 and ACT3 mediate homodimerization via conserved helix residues, while ACT2 and ACT4 form the arginine-binding pocket; mutagenesis of key binding-pocket residues validates their functional roles in arginine-dependent mTORC1 activation. |
X-ray crystallography (2.5 Å), site-directed mutagenesis, biochemical assays |
Cell discovery |
High |
27648300
|
| 2018 |
Comparison of arginine-bound (2.05 Å) and ligand-free (2.8 Å) CASTOR1 crystal structures reveals near-identical conformations except in two loop regions, indicating that CASTOR1 does not undergo large conformational change upon arginine binding; arginine sensing is thus interpreted as a subtle loop-based mechanism rather than a global domain rearrangement. |
X-ray crystallography (apo and holo structures), structural comparison |
Biochemical and biophysical research communications |
High |
30503338
|
| 2025 |
Cryo-EM structure of the GATOR2–CASTOR1 complex (arginine-free) shows that two MIOS WD40 β-propellers of the GATOR2 cage engage both subunits of a single CASTOR1 homodimer at a negatively charged interface distal to the arginine pocket; arginine-triggered loop ordering in CASTOR1 sterically blocks this MIOS-binding interface, switching off GATOR2 binding and thereby de-repressing GATOR1 and activating mTORC1. |
Cryo-electron microscopy, structural analysis, functional validation |
Nature structural & molecular biology |
High |
40470200 40715445
|
| 2021 |
E3 ubiquitin ligase RNF167 catalyzes K29-linked polyubiquitination and proteasomal degradation of CASTOR1; AKT phosphorylates CASTOR1 at Ser14, which markedly increases CASTOR1 binding to RNF167 (promoting its ubiquitination and degradation) while simultaneously decreasing CASTOR1 affinity for MIOS, resulting in mTORC1 activation independent of arginine. |
Co-immunoprecipitation, ubiquitination assays, phosphorylation site mutagenesis, RNF167 knockdown/overexpression, AKT inhibitor treatment |
Nature communications |
High |
33594058
|
| 2019 |
KSHV-encoded miRNAs miR-K4-5p (and likely miR-K1-5p) directly target the CASTOR1 3′-UTR to suppress CASTOR1 expression; knockdown of these miRNAs restores CASTOR1 protein levels and attenuates mTORC1 activation, establishing a viral miRNA–CASTOR1–GATOR2–mTORC1 axis. |
miRNA target validation (direct targeting of CASTOR1 3′-UTR), miRNA knockdown, CASTOR1/CASTOR2 overexpression, mTORC1 activity assays, soft-agar colony formation |
The Journal of clinical investigation |
Medium |
31305263
|
| 2026 |
CASTOR1 and CASTOR2 both bind arginine and interact with GATOR2 component Mios; arginine binding induces conformational changes at the ACT2–ACT4 interface causing dissociation from Mios; CASTOR1 responds to low arginine concentrations and CASTOR2 to high arginine concentrations, enabling dual-sensor fine-tuning of mTORC1 activity; in C2C12 muscle cells, CASTOR proteins regulate mTORC1 and myogenesis in an arginine-level-dependent manner. |
Biochemical binding assays, structural analysis of conformational changes, arginine dose-response experiments, C2C12 cell knockdown with mTORC1 and myogenesis readouts |
Molecular cell |
High |
41506264
|
| 2022 |
In LPS/IFN-γ-activated microglia, CASTOR1 overexpression inhibits M1 polarization by suppressing mTOR signaling; mTOR activator MHY1485 rescues M1 polarization in CASTOR1-overexpressing cells, placing CASTOR1 upstream of mTOR in microglial polarization. |
CASTOR1 overexpression, mTOR activator (MHY1485) epistasis, M1/M2 marker expression assays in primary microglia |
Metabolic brain disease |
Medium |
36454506
|
| 2025 |
CASTOR1 genetic ablation in a KRAS-driven GEMM (LSL-KRAS G12D) enhances lung tumor incidence and accelerates progression; mechanistically, CASTOR1 loss amplifies mTORC1 signaling (elevated p-4EBP1, p-S6) and augments AKT and ERK activation, revealing crosstalk between PI3K/AKT/mTORC1 and KRAS/ERK pathways; mTORC1 and PI3K inhibitors sensitize CASTOR1-deficient resistant tumors to KRAS G12D-targeted therapy. |
Genetically engineered mouse model (CASTOR1 KO × KRAS G12D), tumor-derived organoids, phospho-protein assays, drug combination rescue |
bioRxivpreprint |
Medium |
40313924
|