دورية أكاديمية
Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells.
| العنوان: | Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells. |
|---|---|
| المؤلفون: | Doxsey DD; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA., Tettoni SD; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA., Egri SB; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA., Shen K; Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA; Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Chan Medical School, Worcester, Massachusetts, USA. Electronic address: Kuang.Shen@umassmed.edu. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2023 Jul; Vol. 299 (7), pp. 104880. Date of Electronic Publication: 2023 Jun 01. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Amino Acids*/metabolism , Mechanistic Target of Rapamycin Complex 1*/metabolism , Monomeric GTP-Binding Proteins*/metabolism, Humans ; Lysosomes/metabolism ; Nucleotides/metabolism ; Signal Transduction/physiology ; Static Electricity |
| مستخلص: | Cells need to coordinate nutrient availability with their growth and proliferation. In eukaryotic cells, this coordination is mediated by the mechanistic target of the rapamycin complex 1 (mTORC1) pathway. mTORC1 activation is regulated by two GTPase units, the Rag GTPase heterodimer and the Rheb GTPase. The RagA-RagC heterodimer controls the subcellular localization of mTORC1, and its nucleotide loading states are strictly controlled by upstream regulators including amino acid sensors. A critical negative regulator of the Rag GTPase heterodimer is GATOR1. In the absence of amino acids, GATOR1 stimulates GTP hydrolysis by the RagA subunit to turn off mTORC1 signaling. Despite the enzymatic specificity of GATOR1 to RagA, a recent cryo-EM structural model of the human GATOR1-Rag-Ragulator complex reveals an unexpected interface between Depdc5, a subunit of GATOR1, and RagC. Currently, there is no functional characterization of this interface, nor do we know its biological relevance. Here, combining structure-function analysis, enzymatic kinetic measurements, and cell-based signaling assays, we identified a critical electrostatic interaction between Depdc5 and RagC. This interaction is mediated by the positively charged Arg-1407 residue on Depdc5 and a patch of negatively charged residues on the lateral side of RagC. Abrogating this interaction impairs the GAP activity of GATOR1 and cellular response to amino acid withdrawal. Our results reveal how GATOR1 coordinates the nucleotide loading states of the Rag GTPase heterodimer, and thus precisely controls cellular behavior in the absence of amino acids. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) |
| معلومات مُعتمدة: | R35 GM146824 United States GM NIGMS NIH HHS |
| فهرسة مساهمة: | Keywords: GATOR1; GTPase activating protein; Rag GTPase; mTOR complex 1 (mTORC1); metabolism |
| المشرفين على المادة: | 0 (Amino Acids) EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) EC 3.6.5.2 (Monomeric GTP-Binding Proteins) 0 (Nucleotides) EC 3.6.1.- (RRAGA protein, human) |
| تواريخ الأحداث: | Date Created: 20230603 Date Completed: 20230802 Latest Revision: 20240307 |
| رمز التحديث: | 20240307 |
| مُعرف محوري في PubMed: | PMC10316081 |
| DOI: | 10.1016/j.jbc.2023.104880 |
| PMID: | 37269949 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
|---|---|
| DOI: | 10.1016/j.jbc.2023.104880 |