TY - JOUR
T1 - Structural basis for the assembly of the Ragulator-Rag GTPase complex
AU - Yonehara, Ryo
AU - Nada, Shigeyuki
AU - Nakai, Tomokazu
AU - Nakai, Masahiro
AU - Kitamura, Ayaka
AU - Ogawa, Akira
AU - Nakatsumi, Hirokazu
AU - Nakayama, Keiichi I.
AU - Li, Songling
AU - Standley, Daron M.
AU - Yamashita, Eiki
AU - Nakagawa, Atsushi
AU - Okada, Masato
N1 - Funding Information:
We thank all members of the Nakagawa and Okada laboratories for their helpful suggestions and comments. This work was supported by JSPS KAKENHI Grant Numbers 15H04296, 26640078, 26114006, 17H06004, and 17K19596, and partially by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and the Japan Agency for Medical Research and Development (AMED). This work was performed using a synchrotron beamline BL44XU at SPring-8 under the Cooperative Research Program of the Institute for Protein Research, Osaka University. Diffraction data were collected at Osaka University beamline BL44XU at SPring-8 (Harima, Japan) under proposal numbers 2015A6500, 2015B6500, 2016A6500, and 2016B6500.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes.
AB - The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes.
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U2 - 10.1038/s41467-017-01762-3
DO - 10.1038/s41467-017-01762-3
M3 - Article
C2 - 29158492
AN - SCOPUS:85034640683
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1625
ER -