Abstract
The heterodimeric Rag GTPases consisting of RagA (or RagB) and RagC (or RagD) are the key regulator activating the target of rapamycin complex 1 (TORC1) in response to the level of amino acids. The heterodimer between GTP-loaded RagA/B and GDP-loaded RagC/D is the most active form that binds Raptor and leads to the activation of TORC1. Here, we present the crystal structure of Gtr1p(GTP)-Gtr2p(GDP), the active yeast Rag GTPase heterodimer. The structure reveals that GTP-to-GDP conversion on Gtr2p results in a large conformational transition of this subunit, including a large scale rearrangement of a long segment whose corresponding region in RagA is involved in binding to Raptor. In addition, the two GTPase domains of the heterodimer are brought to contact with each other, but without causing any conformational change of the Gtr1p subunit. These features explain how the nucleotide-bound statuses of the two GTPases subunits switch the Raptor binding affinity on and off.
Highlights
The heterodimeric GTR GTPase is a key regulator in the amino acid mediated target of rapamycin complex 1 (TORC1) pathway
The heterodimeric Rag GTPases consisting of RagA and RagC are the key regulator activating the target of rapamycin complex 1 (TORC1) in response to the level of amino acids
The G domain of Gtr2pGDP is composed of five -strands and five ␣-helices (Fig. 1B), and its nucleotide-binding site lacks a bound Mg2ϩ ion (Fig. 1C) as a result of a large conformational transition, which is described below in detail
Summary
The heterodimeric GTR GTPase is a key regulator in the amino acid mediated TORC1 pathway. The heterodimeric Rag GTPases consisting of RagA (or RagB) and RagC (or RagD) are the key regulator activating the target of rapamycin complex 1 (TORC1) in response to the level of amino acids. The structure reveals that GTP-to-GDP conversion on Gtr2p results in a large conformational transition of this subunit, including a large scale rearrangement of a long segment whose corresponding region in RagA is involved in binding to Raptor. In comparison with the structure of Gtr1pGMPPNP-Gtr2pGMPPNP, reveals that Gtr2p undergoes significant structural rearrangements upon GTP-to-GDP conversion on Gtr2p These changes involve a long segment including switch I, two -strands, and switch II and accompany positional changes of the two GTPase domains. These observations provide the structural view of how the Rag heterodimeric complex
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