7u8q | pdb_00007u8q
Structure of porcine kidney V-ATPase with SidK, Rotary State 2
Structural highlights
Function[VATA_PIG] Catalytic subunit of the V1 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). In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation (By similarity). May play a role in neurite development and synaptic connectivity (By similarity).[UniProtKB:P38606] Publication Abstract from PubMedV-ATPases are rotary proton pumps that serve as signaling hubs with numerous protein binding partners. CryoEM with exhaustive focused classification allowed detection of endogenous proteins associated with porcine kidney V-ATPase. An extra C subunit was found in approximately 3% of complexes, whereas approximately 1.6% of complexes bound mEAK-7, a protein with proposed roles in dauer formation in nematodes and mTOR signaling in mammals. High-resolution cryoEM of porcine kidney V-ATPase with recombinant mEAK-7 showed that mEAK-7's TLDc domain interacts with V-ATPase's stator, whereas its C-terminal alpha helix binds V-ATPase's rotor. This crosslink would be expected to inhibit rotary catalysis. However, unlike the yeast TLDc protein Oxr1p, exogenous mEAK-7 does not inhibit V-ATPase and mEAK-7 overexpression in cells does not alter lysosomal or phagosomal pH. Instead, cryoEM suggests that the mEAK-7:V-ATPase interaction is disrupted by ATP-induced rotation of the rotor. Comparison of Oxr1p and mEAK-7 binding explains this difference. These results show that V-ATPase binding by TLDc domain proteins can lead to effects ranging from strong inhibition to formation of labile interactions that are sensitive to the enzyme's activity. CryoEM of endogenous mammalian V-ATPase interacting with the TLDc protein mEAK-7.,Tan YZ, Abbas YM, Wu JZ, Wu D, Keon KA, Hesketh GG, Bueler SA, Gingras AC, Robinson CV, Grinstein S, Rubinstein JL Life Sci Alliance. 2022 Jul 6;5(11). pii: 5/11/e202201527. doi:, 10.26508/lsa.202201527. Print 2022 Nov. PMID:35794005[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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