6wm3
Human V-ATPase in state 2 with SidK and ADP
Structural highlights
DiseaseVPP1_HUMAN Non-specific syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. FunctionVPP1_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 transports protons across cellular membranes. V-ATPase is responsible for the acidification of various organelles, such as lysosomes, endosomes, the trans-Golgi network, and secretory granules, including synaptic vesicles (PubMed:33065002, PubMed:33833240, PubMed:34909687). In certain cell types, can be exported to the plasma membrane, where it is involved in the acidification of the extracellular environment (By similarity). Required for assembly and activity of the vacuolar ATPase (By similarity). Through its action on compartment acidification, plays an essential role in neuronal development in terms of integrity and connectivity of neurons (PubMed:33833240).[UniProtKB:P32563][UniProtKB:Q29466][1] [2] [3] Publication Abstract from PubMedVesicular- or vacuolar-type adenosine triphosphatases (V-ATPases) are ATP-driven proton pumps comprised of a cytoplasmic V1 complex for ATP hydrolysis and a membrane-embedded Vo complex for proton transfer. They play important roles in acidification of intracellular vesicles, organelles, and the extracellular milieu in eukaryotes. Here, we report cryoelectron microscopy structures of human V-ATPase in three rotational states at up to 2.9-A resolution. Aided by mass spectrometry, we build all known protein subunits with associated N-linked glycans and identify glycolipids and phospholipids in the Vo complex. We define ATP6AP1 as a structural hub for Vo complex assembly because it connects to multiple Vo subunits and phospholipids in the c-ring. The glycolipids and the glycosylated Vo subunits form a luminal glycan coat critical for V-ATPase folding, localization, and stability. This study identifies mechanisms of V-ATPase assembly and biogenesis that rely on the integrated roles of ATP6AP1, glycans, and lipids. Structures of a Complete Human V-ATPase Reveal Mechanisms of Its Assembly.,Wang L, Wu D, Robinson CV, Wu H, Fu TM Mol Cell. 2020 Nov 5;80(3):501-511.e3. doi: 10.1016/j.molcel.2020.09.029. Epub, 2020 Oct 15. PMID:33065002[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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