Journal Article

Mechanism of arginine sensing by CASTOR1 upstream of mTORC1

Sabatini, David M., Schwartz, Thomas U., Chantranupong, Lynne, Saxton, Robert A., Knockenhauer, Kevin E.

2016

Overview

Structural data on the protein CASTOR1 reveal how the mTORC1 pathway senses intracellular arginine, suggesting a repurposing of an evolutionarily pre-metazoan mechanism. Structure of human CASTOR1 bound to arginine The mTOR pathway is a major regulator of cell growth and is deregulated in numerous diseases. It is influenced by various environmental inputs such as amino acids and growth factors. Availability of arginine can be relayed to mTORC1 through the protein CASTOR1 that interacts with the regulator GATOR2. Here, David Sabatini and colleagues present a crystal structure of arginine bound to CASTOR1. The structure and accompanying biochemistry reveal how arginine is specifically sensed by CASTOR1 and disrupts the interaction of CASTOR1 with GATOR2, triggering activation of mTORC1. CASTOR1 is structurally homologous to the lysine-binding domain of prokaryotic aspartate kinases. These results therefore establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor. The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids 1 , 2 , 3 . In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4 , 5 , 6 , 7 ).Arginine activates mTORC1 upstream of the Rag family of GTPases 8 , through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting C ellular A rginine S ensor for m TOR C1 (CASTOR1) 9 , 10 , 11 , 12 . However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two A spartate kinase, C horismate mutase, T yrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/535/1266 / 631/80/83/2359 / 631/80/86/2369 / 82/83 / 96/1 / 96/106 / 96/109 / 96/95 / Allosteric Regulation - drug effects / Allosteric Site - drug effects / Amino acids / Arginine / Arginine - chemistry / Arginine - deficiency / Arginine - metabolism / Arginine - pharmacology / Aspartate Kinase - chemistry / Aspartate Kinase - metabolism / Carrier Proteins - chemistry / Carrier Proteins - metabolism / Crystal structure / Crystallography, X-Ray / Enzyme Activation - drug effects / Evolution, Molecular / Growth factors / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins / Kinases / letter / Ligands / Lysine - metabolism / Mammals / Mechanistic Target of Rapamycin Complex 1 / Models, Molecular / Molecular biology / multidisciplinary / Multiprotein Complexes - chemistry / Multiprotein Complexes - metabolism / Nutrients / Physiological aspects / Protein Binding - drug effects / Protein kinases / Protein Multimerization / Protein Structure, Tertiary / Science / Signal Transduction - drug effects / TOR Serine-Threonine Kinases - chemistry / TOR Serine-Threonine Kinases - metabolism / Upstream