PDBsum entry 5i2c

Signaling protein

PDB id: 5i2c

Contents

Protein chains

301 a.a.

283 a.a.

285 a.a.

Ligands

ARG ×4

ACT ×4

Waters ×796

PDB id:

5i2c

Name:

Signaling protein

Title:

Arginine-bound castor1 from homo sapiens

Structure:

Gats-like protein 3. Chain: a, b, c, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gatsl3. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: lobstr

Resolution:

1.80Å R-factor: 0.172 R-free: 0.204

Authors:

R.A.Saxton,K.E.Knockenhauer,T.U.Schwartz

Key ref:

R.A.Saxton et al. (2016). Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature, 536, 229-233. PubMed id: 27487210 DOI: 10.1038/nature19079

Date:

08-Feb-16 Release date: 10-Aug-16

Protein chain

Q8WTX7  (CAST1_HUMAN) -  Cytosolic arginine sensor for mTORC1 subunit 1 from Homo sapiens

Seq: 329 a.a.

Struc: 301 a.a.

Protein chain

Q8WTX7  (CAST1_HUMAN) -  Cytosolic arginine sensor for mTORC1 subunit 1 from Homo sapiens

Seq: 329 a.a.

Struc: 283 a.a.

Protein chains

Q8WTX7  (CAST1_HUMAN) -  Cytosolic arginine sensor for mTORC1 subunit 1 from Homo sapiens

Seq: 329 a.a.

Struc: 285 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.?

DOI no: 10.1038/nature19079

Nature 536:229-233 (2016)

PubMed id: 27487210

Mechanism of arginine sensing by CASTOR1 upstream of mTORC1.

R.A.Saxton, L.Chantranupong, K.E.Knockenhauer, T.U.Schwartz, D.M.Sabatini.

ABSTRACT

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. 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, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). 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 Aspartate kinase, Chorismate mutase, TyrA (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.