9KPG

Crystal structure of human CASTOR2-arginine

Summary for 9KPG

• Entry DOI: 10.2210/pdb9kpg/pdb
• Related: 9KP4 9KPB
• Descriptor: Cytosolic arginine sensor for mTORC1 subunit 2, ARGININE, POTASSIUM ION, ... (4 entities in total)
• Functional Keywords: castor2, mtorc1, castor, signaling protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 74940.85

Authors

Liu, C.,Ding, J.,Zhang, T. (deposition date: 2024-11-22, release date: 2026-03-25)

Primary citation

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, 86:362-375.e4, 2026

PubMed Abstract: 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.

PubMed: 41506264
DOI: 10.1016/j.molcel.2025.12.016

Experimental method

X-RAY DIFFRACTION (1.85 Å)