7unf
CryoEM structure of a mEAK7 bound human V-ATPase complex
Structural highlights
DiseaseVPP4_HUMAN Autosomal recessive distal renal tubular acidosis. The disease is caused by variants affecting the gene represented in this entry. FunctionVPP4_HUMAN Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons (By similarity). V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment (By similarity). Involved in normal vectorial acid transport into the urine by the kidney (PubMed:10973252, PubMed:12414817).[UniProtKB:Q29466][UniProtKB:Q93050][1] [2] Publication Abstract from PubMedThe 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. Molecular basis of mEAK7-mediated human V-ATPase regulation.,Wang R, Qin Y, Xie XS, Li X Nat Commun. 2022 Jun 7;13(1):3272. doi: 10.1038/s41467-022-30899-z. PMID:35672408[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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