Arginine Activates mTORC1 through Allosteric Control of CASTOR1

The mTOR pathway orchestrates metabolic processes in response to levels of growth factors and nutrients and is commonly deregulated in human tumors. The amino acid arginine has many critical physiologic functions that are primarily mediated through activation of mTOR complex 1 (mTORC1) downstream of either the lysosomal amino acid transporter SLC38A9 or the cellular arginine sensor for mTORC1 (CASTOR1), but the molecular mechanism underlying detection of arginine and subsequent signaling to mTORC1 has remained unclear. Saxton and colleagues determined the crystal structure of arginine-bound CASTOR1 to 1.8 Å resolution and found that CASTOR1 has four tandem aspartate kinase, chorismate mutase, TyrA (ACT) domains, forms a homodimer, and binds arginine at the interface of two ACT domains (ACT2 and ACT4). In the absence of arginine, the CASTOR1 homodimer suppresses mTORC1 activation by binding and inhibiting GATOR2, a protein complex that activates the RAS-related guanosine triphosphatase (RAG) proteins that mediate mTORC1 translocation to the site of its activation on the surface of the lysosome. However, arginine binding induces a conformational change in the ACT2–ACT4 interface that alters the position of residues required for GATOR2 binding, thus promoting the dissociation of CASTOR1 from GATOR2 and subsequently leading to mTORC1 activation. These structural insights provide a molecular basis for arginine sensing by the mTOR pathway and have the potential to guide development of compounds that can modulate abnormal mTORC1 activity through upstream disruption of arginine sensing by CASTOR1.

Saxton RA, Chantranupong L, Knockenhauer KE, Schwartz TU, Sabatini DM. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 2016 Aug 3 [Epub ahead of print].