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Title: Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex

Abstract

The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. In this study, the crystal structure of the five-subunit human Ragulator at 1.4 Å resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagAGTP:RagCGDPdimer bound to Ragulator at 16 Å resolution, revealing that the G-domains of the Rags project away from the Ragulator core. Lastly, the combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity.

Authors:
 [1];  [1];  [1];  [1];  [1];  [2];  [3];  [2]
  1. Univ. of California, Berkeley, CA (United States). Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences
  2. Univ. of California, Berkeley, CA (United States). Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences ; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrated Bioimaging Division
  3. Univ. of California, Berkeley, CA (United States). Department of Molecular and Cell Biology and California Institute for Quantitative Biosciences and The Paul F. Glenn Center for Aging Research
Publication Date:
Research Org.:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1484843
Alternate Identifier(s):
OSTI ID: 1426747
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 68; Journal Issue: 5; Journal ID: ISSN 1097-2765
Publisher:
Cell Press - Elsevier
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Su, Ming-Yuan, Morris, Kyle L., Kim, Do Jin, Fu, Yangxue, Lawrence, Rosalie, Stjepanovic, Goran, Zoncu, Roberto, and Hurley, James H. Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. United States: N. p., 2017. Web. doi:10.1016/j.molcel.2017.10.016.
Su, Ming-Yuan, Morris, Kyle L., Kim, Do Jin, Fu, Yangxue, Lawrence, Rosalie, Stjepanovic, Goran, Zoncu, Roberto, & Hurley, James H. Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. United States. https://doi.org/10.1016/j.molcel.2017.10.016
Su, Ming-Yuan, Morris, Kyle L., Kim, Do Jin, Fu, Yangxue, Lawrence, Rosalie, Stjepanovic, Goran, Zoncu, Roberto, and Hurley, James H. Tue . "Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex". United States. https://doi.org/10.1016/j.molcel.2017.10.016.
@article{osti_1484843,
title = {Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex},
author = {Su, Ming-Yuan and Morris, Kyle L. and Kim, Do Jin and Fu, Yangxue and Lawrence, Rosalie and Stjepanovic, Goran and Zoncu, Roberto and Hurley, James H.},
abstractNote = {The lysosomal membrane is the locus for sensing cellular nutrient levels, which are transduced to mTORC1 via the Rag GTPases and the Ragulator complex. In this study, the crystal structure of the five-subunit human Ragulator at 1.4 Å resolution was determined. Lamtor1 wraps around the other four subunits to stabilize the assembly. The Lamtor2:Lamtor3 dimer stacks upon Lamtor4:Lamtor5 to create a platform for Rag binding. Hydrogen-deuterium exchange was used to map the Rag binding site to the outer face of the Lamtor2:Lamtor3 dimer and to the N-terminal intrinsically disordered region of Lamtor1. EM was used to reconstruct the assembly of the full-length RagAGTP:RagCGDPdimer bound to Ragulator at 16 Å resolution, revealing that the G-domains of the Rags project away from the Ragulator core. Lastly, the combined structural model shows how Ragulator functions as a platform for the presentation of active Rags for mTORC1 recruitment, and might suggest an unconventional mechanism for Rag GEF activity.},
doi = {10.1016/j.molcel.2017.10.016},
journal = {Molecular Cell},
number = 5,
volume = 68,
place = {United States},
year = {2017},
month = {12}
}

Journal Article:
Free Publicly Available Full Text
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https://doi.org/10.1016/j.molcel.2017.10.016

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