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

Author:

Wang Longfei1234,Wu Di56,Robinson Carol V.56ORCID,Fu Tian-Min78ORCID

Affiliation:

1. Department of Cardiology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China

2. Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China

3. Department of Cardiovascular Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China

4. Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China

5. Department of Chemistry, University of Oxford, Oxford OX1 3QZ, United Kingdom

6. Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford OX1 3QZ, United Kingdom

7. Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210

8. The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210

Abstract

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.

Funder

HHS | NIH | National Institute of General Medical Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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