7unf

CryoEM structure of a mEAK7 bound human V-ATPase complexCryoEM structure of a mEAK7 bound human V-ATPase complex

Structural highlights

7unf is a 18 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.08Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

VPP4_HUMAN Autosomal recessive distal renal tubular acidosis. The disease is caused by variants affecting the gene represented in this entry.

Function

VPP4_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 PubMed

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.

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.

References

↑ Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet. 2000 Sep;26(1):71-5. PMID:10973252 doi:10.1038/79208
↑ Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, Giersch AB, Morton CC, Axon PR, Akil I, Al-Sabban EA, Baguley DM, Bianca S, Bakkaloglu A, Bircan Z, Chauveau D, Clermont MJ, Guala A, Hulton SA, Kroes H, Li Volti G, Mir S, Mocan H, Nayir A, Ozen S, Rodriguez Soriano J, Sanjad SA, Tasic V, Taylor CM, Topaloglu R, Smith AN, Karet FE. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet. 2002 Nov;39(11):796-803. PMID:12414817 doi:10.1136/jmg.39.11.796
↑ Wang R, Qin Y, Xie XS, Li X. Molecular basis of mEAK7-mediated human V-ATPase regulation. Nat Commun. 2022 Jun 7;13(1):3272. PMID:35672408 doi:10.1038/s41467-022-30899-z

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OCA

[1] Smith AN, Skaug J, Choate KA, Nayir A, Bakkaloglu A, Ozen S, Hulton SA, Sanjad SA, Al-Sabban EA, Lifton RP, Scherer SW, Karet FE. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet. 2000 Sep;26(1):71-5. PMID:10973252 doi:10.1038/79208

[2] Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, Giersch AB, Morton CC, Axon PR, Akil I, Al-Sabban EA, Baguley DM, Bianca S, Bakkaloglu A, Bircan Z, Chauveau D, Clermont MJ, Guala A, Hulton SA, Kroes H, Li Volti G, Mir S, Mocan H, Nayir A, Ozen S, Rodriguez Soriano J, Sanjad SA, Tasic V, Taylor CM, Topaloglu R, Smith AN, Karet FE. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet. 2002 Nov;39(11):796-803. PMID:12414817 doi:10.1136/jmg.39.11.796

[3] Wang R, Qin Y, Xie XS, Li X. Molecular basis of mEAK7-mediated human V-ATPase regulation. Nat Commun. 2022 Jun 7;13(1):3272. PMID:35672408 doi:10.1038/s41467-022-30899-z

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