Molecular basis of mEAK7-mediated human V-ATPase regulation

The activity of V-ATPase is well-known to be regulated by reversible dissociation of its V 1 and V o domains in response to growth factor stimulation, nutrient sensing, and cellular differentiation. The molecular basis of its regulation by an endogenous modulator without affecting V-ATPase assembly...

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Bibliographic Details
Published in:Nature communications 2022-06, Vol.13 (1), p.3272-3272, Article 3272
Main Authors: Wang, Rong, Qin, Yu, Xie, Xiao-Song, Li, Xiaochun
Format: Article
Language:English
Subjects:
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Adenosine triphosphatase
AKT protein
AKT1 protein
Differentiation (biology)
Growth factors
H+-transporting ATPase
Humanities and Social Sciences
Lipids
Mammals
multidisciplinary
Na+/K+-exchanging ATPase
Phosphorylation
Proteins
Ribosomal protein S6
Science
Science (multidisciplinary)
Signal transduction
TOR protein
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Summary:The activity of V-ATPase is well-known to be regulated by reversible dissociation of its V 1 and V o domains in response to growth factor stimulation, nutrient sensing, and cellular differentiation. The molecular basis of its regulation by an endogenous modulator without affecting V-ATPase assembly remains unclear. Here, we discover that a lysosome-anchored protein termed (mammalian Enhancer-of-Akt-1-7 (mEAK7)) binds to intact V-ATPase. We determine cryo-EM structure of human mEAK7 in complex with human V-ATPase in native lipid-containing nanodiscs. The structure reveals that the TLDc domain of mEAK7 engages with subunits A, B, and E, while its C-terminal domain binds to subunit D, presumably blocking V 1 – V o torque transmission. Our functional studies suggest that mEAK7, which may act as a V-ATPase inhibitor, does not affect the activity of V-ATPase in vitro. However, overexpression of mEAK7 in HCT116 cells that stably express subunit a4 of V-ATPase represses the phosphorylation of ribosomal protein S6. Thus, this finding suggests that mEAK7 potentially links mTOR signaling with V-ATPase activity. Structural basis of V-ATPase regulation by endogenous proteins is unclear. Here, the authors find mEAK7 as an endogenous V-ATPase modulator and determine its structure with V-ATPase, suggesting the potential role of mEAK7 in V-ATPase regulation.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-30899-z