Breaking Up and Making Up: The Secret Life of the Vacuolar H -ATPase

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2017 Mar 2

PMID 28247968

Citations 36

Authors

Rebecca A Oot

Sergio Couoh-Cardel

Stuti Sharma

Nicholas J Stam

Stephan Wilkens

Affiliations

Soon will be listed here.

Abstract

The vacuolar ATPase (V-ATPase; V V -ATPase) is a large multisubunit proton pump found in the endomembrane system of all eukaryotic cells where it acidifies the lumen of subcellular organelles including lysosomes, endosomes, the Golgi apparatus, and clathrin-coated vesicles. V-ATPase function is essential for pH and ion homeostasis, protein trafficking, endocytosis, mechanistic target of rapamycin (mTOR), and Notch signaling, as well as hormone secretion and neurotransmitter release. V-ATPase can also be found in the plasma membrane of polarized animal cells where its proton pumping function is involved in bone remodeling, urine acidification, and sperm maturation. Aberrant (hypo or hyper) activity has been associated with numerous human diseases and the V-ATPase has therefore been recognized as a potential drug target. Recent progress with moderate to high-resolution structure determination by cryo electron microscopy and X-ray crystallography together with sophisticated single-molecule and biochemical experiments have provided a detailed picture of the structure and unique mode of regulation of the V-ATPase. This review summarizes the recent advances, focusing on the structural and biophysical aspects of the field.

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References

Murata T, Yamato I, Kakinuma Y, Leslie A, Walker J . Structure of the rotor of the V-Type Na+-ATPase from Enterococcus hirae. Science. 2005; 308(5722):654-9. DOI: 10.1126/science.1110064. View

Peters C, Bayer M, Buhler S, Andersen J, Mann M, Mayer A . Trans-complex formation by proteolipid channels in the terminal phase of membrane fusion. Nature. 2001; 409(6820):581-8. DOI: 10.1038/35054500. View

Nakano M, Imamura H, Toei M, Tamakoshi M, Yoshida M, Yokoyama K . ATP hydrolysis and synthesis of a rotary motor V-ATPase from Thermus thermophilus. J Biol Chem. 2008; 283(30):20789-96. PMC: 3258951. DOI: 10.1074/jbc.M801276200. View

Rawson S, Phillips C, Huss M, Tiburcy F, Wieczorek H, Trinick J . Structure of the vacuolar H+-ATPase rotary motor reveals new mechanistic insights. Structure. 2015; 23(3):461-471. PMC: 4353692. DOI: 10.1016/j.str.2014.12.016. View

Smardon A, Nasab N, Tarsio M, Diakov T, Kane P . Molecular Interactions and Cellular Itinerary of the Yeast RAVE (Regulator of the H+-ATPase of Vacuolar and Endosomal Membranes) Complex. J Biol Chem. 2015; 290(46):27511-23. PMC: 4646003. DOI: 10.1074/jbc.M115.667634. View

Smardon A, Diab H, Tarsio M, Diakov T, Nasab N, West R . The RAVE complex is an isoform-specific V-ATPase assembly factor in yeast. Mol Biol Cell. 2013; 25(3):356-67. PMC: 3907276. DOI: 10.1091/mbc.E13-05-0231. View

Smith A, Skaug J, Choate K, Nayir A, Bakkaloglu A, Ozen S . 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; 26(1):71-5. DOI: 10.1038/79208. View

Xu Y, Parmar A, Roux E, Balbis A, Dumas V, Chevalier S . Epidermal growth factor-induced vacuolar (H+)-atpase assembly: a role in signaling via mTORC1 activation. J Biol Chem. 2012; 287(31):26409-22. PMC: 3406724. DOI: 10.1074/jbc.M112.352229. View

Sagermann M, Stevens T, Matthews B . Crystal structure of the regulatory subunit H of the V-type ATPase of Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2001; 98(13):7134-9. PMC: 34635. DOI: 10.1073/pnas.131192798. View

10.

Wilkens S, Vasilyeva E, Forgac M . Structure of the vacuolar ATPase by electron microscopy. J Biol Chem. 1999; 274(45):31804-10. DOI: 10.1074/jbc.274.45.31804. View

11.

Iwata M, Imamura H, Stambouli E, Ikeda C, Tamakoshi M, Nagata K . Crystal structure of a central stalk subunit C and reversible association/dissociation of vacuole-type ATPase. Proc Natl Acad Sci U S A. 2003; 101(1):59-64. PMC: 314138. DOI: 10.1073/pnas.0305165101. View

12.

Geyer M, Yu H, Mandic R, Linnemann T, Zheng Y, Fackler O . Subunit H of the V-ATPase binds to the medium chain of adaptor protein complex 2 and connects Nef to the endocytic machinery. J Biol Chem. 2002; 277(32):28521-9. DOI: 10.1074/jbc.M200522200. View

13.

Wilkens S . Rotary molecular motors. Adv Protein Chem. 2005; 71:345-82. DOI: 10.1016/S0065-3233(04)71009-8. View

14.

Wilkens S, Inoue T, Forgac M . Three-dimensional structure of the vacuolar ATPase. Localization of subunit H by difference imaging and chemical cross-linking. J Biol Chem. 2004; 279(40):41942-9. DOI: 10.1074/jbc.M407821200. View

15.

Morel N, Poea-Guyon S . The membrane domain of vacuolar H(+)ATPase: a crucial player in neurotransmitter exocytotic release. Cell Mol Life Sci. 2015; 72(13):2561-73. PMC: 11113229. DOI: 10.1007/s00018-015-1886-2. View

16.

Nishi T, Kawasaki-Nishi S, Forgac M . The first putative transmembrane segment of subunit c" (Vma16p) of the yeast V-ATPase is not necessary for function. J Biol Chem. 2002; 278(8):5821-7. DOI: 10.1074/jbc.M209875200. View

17.

Parra K, Chan C, Chen J . Saccharomyces cerevisiae vacuolar H+-ATPase regulation by disassembly and reassembly: one structure and multiple signals. Eukaryot Cell. 2014; 13(6):706-14. PMC: 4054264. DOI: 10.1128/EC.00050-14. View

18.

Inoue H, Noumi T, Nagata M, Murakami H, Kanazawa H . Targeted disruption of the gene encoding the proteolipid subunit of mouse vacuolar H(+)-ATPase leads to early embryonic lethality. Biochim Biophys Acta. 1999; 1413(3):130-8. DOI: 10.1016/s0005-2728(99)00096-1. View

19.

Sautin Y, Lu M, Gaugler A, Zhang L, Gluck S . Phosphatidylinositol 3-kinase-mediated effects of glucose on vacuolar H+-ATPase assembly, translocation, and acidification of intracellular compartments in renal epithelial cells. Mol Cell Biol. 2005; 25(2):575-89. PMC: 543406. DOI: 10.1128/MCB.25.2.575-589.2005. View

20.

Zhang Z, Zheng Y, Mazon H, Milgrom E, Kitagawa N, Kish-Trier E . Structure of the yeast vacuolar ATPase. J Biol Chem. 2008; 283(51):35983-95. PMC: 2602884. DOI: 10.1074/jbc.M805345200. View