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Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining

Vacuolar-type adenosine triphosphatases (V-ATPases) not only function as rotary proton pumps in cellular organelles but also serve as signaling hubs. To identify the endogenous binding partners of V-ATPase, we collected a large dataset of human V-ATPases and did extensive classification and focused...

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Autores principales: Wang, Longfei, Wu, Di, Robinson, Carol V., Fu, Tian-Min
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436323/
https://www.ncbi.nlm.nih.gov/pubmed/35994636
http://dx.doi.org/10.1073/pnas.2203742119
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author Wang, Longfei
Wu, Di
Robinson, Carol V.
Fu, Tian-Min
author_facet Wang, Longfei
Wu, Di
Robinson, Carol V.
Fu, Tian-Min
author_sort Wang, Longfei
collection PubMed
description Vacuolar-type adenosine triphosphatases (V-ATPases) not only function as rotary proton pumps in cellular organelles but also serve as signaling hubs. To identify the endogenous binding partners of V-ATPase, we collected a large dataset of human V-ATPases and did extensive classification and focused refinement of human V-ATPases. Unexpectedly, about 17% of particles in state 2 of human V-ATPases display additional density with an overall resolution of 3.3 Å. Structural analysis combined with artificial intelligence modeling enables us to identify this additional density as mEAK-7, a protein involved in mechanistic target of rapamycin (mTOR) signaling in mammals. Our structure shows that mEAK-7 interacts with subunits A, B, D, and E of V-ATPases in state 2. Thus, we propose that mEAK-7 may regulate V-ATPase function through binding to V-ATPases in state 2 as well as mediate mTOR signaling.
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spelling pubmed-94363232022-09-02 Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining Wang, Longfei Wu, Di Robinson, Carol V. Fu, Tian-Min Proc Natl Acad Sci U S A Biological Sciences Vacuolar-type adenosine triphosphatases (V-ATPases) not only function as rotary proton pumps in cellular organelles but also serve as signaling hubs. To identify the endogenous binding partners of V-ATPase, we collected a large dataset of human V-ATPases and did extensive classification and focused refinement of human V-ATPases. Unexpectedly, about 17% of particles in state 2 of human V-ATPases display additional density with an overall resolution of 3.3 Å. Structural analysis combined with artificial intelligence modeling enables us to identify this additional density as mEAK-7, a protein involved in mechanistic target of rapamycin (mTOR) signaling in mammals. Our structure shows that mEAK-7 interacts with subunits A, B, D, and E of V-ATPases in state 2. Thus, we propose that mEAK-7 may regulate V-ATPase function through binding to V-ATPases in state 2 as well as mediate mTOR signaling. National Academy of Sciences 2022-08-22 2022-08-30 /pmc/articles/PMC9436323/ /pubmed/35994636 http://dx.doi.org/10.1073/pnas.2203742119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Wang, Longfei
Wu, Di
Robinson, Carol V.
Fu, Tian-Min
Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title_full Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title_fullStr Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title_full_unstemmed Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title_short Identification of mEAK-7 as a human V-ATPase regulator via cryo-EM data mining
title_sort identification of meak-7 as a human v-atpase regulator via cryo-em data mining
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436323/
https://www.ncbi.nlm.nih.gov/pubmed/35994636
http://dx.doi.org/10.1073/pnas.2203742119
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