v-ATPase

V-ATPases are found within the membranes of many organelles, such as endosomes, lysosomes, and secretory vesicles, where they play a variety of roles crucial for the function of these organelles. For example, the proton gradient across the yeast vacuolar membrane generated by V-ATPases drives calcium uptake into the vacuole through an {{chem|H|+|/Ca|2+}} antiporter system.{{cite journal | vauthors = Ohya Y, Umemoto N, Tanida I, Ohta A, Iida H, Anraku Y | title = Calcium-sensitive cls mutants of Saccharomyces cerevisiae showing a Pet- phenotype are ascribable to defects of vacuolar membrane H(+)-ATPase activity | journal = The Journal of Biological Chemistry | volume = 266 | issue = 21 | pages = 13971–7 | date = July 1991 | doi = 10.1016/S0021-9258(18)92798-5 | pmid = 1830311 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1830311 | doi-access = free }} In synaptic transmission in neuronal cells, V-ATPase acidifies synaptic vesicles.{{cite journal | vauthors = Wienisch M, Klingauf J | title = Vesicular proteins exocytosed and subsequently retrieved by compensatory endocytosis are nonidentical | journal = Nature Neuroscience | volume = 9 | issue = 8 | pages = 1019–27 | date = August 2006 | pmid = 16845386 | doi = 10.1038/nn1739 | hdl = 11858/00-001M-0000-0012-E436-F | s2cid = 12808314 | hdl-access = free }} Norepinephrine enters vesicles by V-ATPase {{Citation needed|date=February 2022}}.

V-ATPases are also found in the plasma membranes of a wide variety of cells such as intercalated cells of the kidney, osteoclasts (bone resorbing cells), macrophages, neutrophils, sperm, midgut cells of insects, and certain tumor cells.{{cite journal | vauthors = Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K | title = Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy | journal = Cancer Treatment Reviews | volume = 29 | issue = 6 | pages = 541–9 | date = December 2003 | pmid = 14585264 | doi = 10.1016/S0305-7372(03)00106-3 }} Plasma membrane V-ATPases are involved in processes such as pH homeostasis, coupled transport, and tumor metastasis. V-ATPases in the acrosomal membrane of sperm acidify the acrosome. This acidification activates proteases required to drill through the plasma membrane of the egg. V-ATPases in the osteoclast plasma membrane pump protons onto the bone surface, which is necessary for bone resorption. In the intercalated cells of the kidney, V-ATPases pump protons into the urine, allowing for bicarbonate reabsorption into the blood. In addition, other variety of biological processes, such as toxin delivery, viral entry, membrane targeting, apoptosis, regulation of cytoplasmic pH, proteolytic process, and acidification of intracellular systems, are important roles of V-ATPases.{{cite journal | vauthors = Emma B, Forest O, Barry B | title = Mutations of pma-1, the Gene Encoding the Plasma Membrane H+ATPase of Neurospora crassa, Suppress Inhibition of Growth by Concanamycin A, a Specific Inhibitor of Vacuolar ATPases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 23 | pages = 14776–14786 | date = June 1997 | pmid = 9169444 | doi = 10.1074/jbc.272.23.14776 | s2cid = 29865381 | doi-access = free }}

V-ATPases also play a significant role in cell morphogenesis development. Disruption of the gene vma-1 gene which encodes for the catalytic subunit (A) of the enzyme severely impairs the rate of growth, differentiation, and the capacity to produce viable spores in fungus Neurospora crassa. Bowman, E. J., & Bowman, B. J. (2000). Cellular role of the V-ATPase in Neurospora crassa: analysis of mutants resistant to concanamycin or lacking the catalytic subunit A. The Journal of experimental biology, 203(Pt 1), 97–106.

The yeast V-ATPase is the best characterized. There are at least thirteen subunits identified to form a functional V-ATPase complex, which consists of two domains. The subunits belong to either the V_o domain (membrane associated subunits, lowercase letters on the figure) or the V₁ domain (peripherally associated subunits, uppercase letters on the figure).

The V₁ includes eight subunits, A-H, with three copies of the catalytic A and B subunits, three copies of the stator subunits E and G, and one copy of the regulatory C and H subunits. In addition, the V₁ domain also contains the subunits D and F, which form a central rotor axle.{{cite journal | vauthors = Kitagawa N, Mazon H, Heck AJ, Wilkens S | title = Stoichiometry of the peripheral stalk subunits E and G of yeast V1-ATPase determined by mass spectrometry | journal = The Journal of Biological Chemistry | volume = 283 | issue = 6 | pages = 3329–37 | date = February 2008 | pmid = 18055462 | doi = 10.1074/jbc.M707924200 | s2cid = 27627066 | doi-access = free }} The V₁ domain contains tissue-specific subunit isoforms including B, C, E, and G. Mutations to the B1 isoform result in the human disease distal renal tubular acidosis and sensorineural deafness.

The V_o domain contains six different subunits, a, d, c, c', c", and e, with the stoichiometry of the c ring still a matter of debate with a decamer being postulated for the tobacco hornworm (Manduca sexta) V-ATPase. The mammalian V_o domain contains tissue-specific isoforms for subunits a and d, while yeast V-ATPase contains two organelle-specific subunit isoforms of a, Vph1p, and Stv1p. Mutations to the a3 isoform result in the human disease infantile malignant osteopetrosis, and mutations to the a4 isoform result in distal renal tubular acidosis, in some cases with sensorineural deafness.

The V₁ domain is responsible for ATP hydrolysis, whereas the V_o domain is responsible for proton translocation. ATP hydrolysis at the catalytic nucleotide binding sites on subunit A drives rotation of a central stalk composed of subunits D and F, which in turn drives rotation of a barrel of c subunits relative to the a subunit. The complex structure of the V-ATPase has been revealed through the structure of the M. Sexta and Yeast complexes that were solved by single-particle cryo-EM and negative staining, respectively.{{cite journal | vauthors = Muench SP, Huss M, Song CF, Phillips C, Wieczorek H, Trinick J, Harrison MA | title = Cryo-electron microscopy of the vacuolar ATPase motor reveals its mechanical and regulatory complexity | journal = Journal of Molecular Biology | volume = 386 | issue = 4 | pages = 989–99 | date = March 2009 | pmid = 19244615 | doi = 10.1016/j.jmb.2009.01.014 }}{{cite journal | vauthors = Diepholz M, Börsch M, Böttcher B | title = Structural organization of the V-ATPase and its implications for regulatory assembly and disassembly | journal = Biochemical Society Transactions | volume = 36 | issue = Pt 5 | pages = 1027–31 | date = October 2008 | pmid = 18793183 | doi = 10.1042/BST0361027 | s2cid = 23852611 }}{{cite journal | vauthors = Zhang Z, Zheng Y, Mazon H, Milgrom E, Kitagawa N, Kish-Trier E, Heck AJ, Kane PM, Wilkens S | title = Structure of the yeast vacuolar ATPase | journal = The Journal of Biological Chemistry | volume = 283 | issue = 51 | pages = 35983–95 | date = December 2008 | pmid = 18955482 | pmc = 2602884 | doi = 10.1074/jbc.M805345200 | doi-access = free }} These structures have revealed that the V-ATPase has a 3-stator network, linked by a collar of density formed by the C, H, and a subunits, which, while dividing the V₁ and V_o domains, make no interactions with the central rotor axle formed by the F, D, and d subunits. Rotation of this central rotor axle caused by the hydrolysis of ATP within the catalytic AB domains results in the movement of the barrel of c subunits past the a subunit, which drives proton transport across the membrane. A stoichiometry of two protons translocated for each ATP hydrolyzed has been proposed by Johnson.{{cite journal | vauthors = Johnson RG, Beers MF, Scarpa A | title = H+ ATPase of chromaffin granules. Kinetics, regulation, and stoichiometry | journal = The Journal of Biological Chemistry | volume = 257 | issue = 18 | pages = 10701–7 | date = September 1982 | doi = 10.1016/S0021-9258(18)33879-1 | pmid = 6213624 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=6213624 | doi-access = free }}

In addition to the structural subunits of yeast V-ATPase, associated proteins that are necessary for assembly have been identified. These associated proteins are essential for V_o domain assembly and are termed Vma12p, Vma21p, and Vma22p.{{cite journal | vauthors = Hirata R, Umemoto N, Ho MN, Ohya Y, Stevens TH, Anraku Y | title = VMA12 is essential for assembly of the vacuolar H(+)-ATPase subunits onto the vacuolar membrane in Saccharomyces cerevisiae | journal = The Journal of Biological Chemistry | volume = 268 | issue = 2 | pages = 961–7 | date = January 1993 | doi = 10.1016/S0021-9258(18)54027-8 | pmid = 8419376 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8419376 | doi-access = free }}{{cite journal | vauthors = Ho MN, Hirata R, Umemoto N, Ohya Y, Takatsuki A, Stevens TH, Anraku Y | title = VMA13 encodes a 54-kDa vacuolar H(+)-ATPase subunit required for activity but not assembly of the enzyme complex in Saccharomyces cerevisiae | journal = The Journal of Biological Chemistry | volume = 268 | issue = 24 | pages = 18286–92 | date = August 1993 | doi = 10.1016/S0021-9258(17)46842-6 | pmid = 8349704 | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8349704 | doi-access = free }}{{cite journal | vauthors = Hill KJ, Stevens TH | title = Vma21p is a yeast membrane protein retained in the endoplasmic reticulum by a di-lysine motif and is required for the assembly of the vacuolar H(+)-ATPase complex | journal = Molecular Biology of the Cell | volume = 5 | issue = 9 | pages = 1039–50 | date = September 1994 | pmid = 7841520 | pmc = 301125 | doi = 10.1091/mbc.5.9.1039 }}{{cite journal | vauthors = Jackson DD, Stevens TH | title = VMA12 encodes a yeast endoplasmic reticulum protein required for vacuolar H+-ATPase assembly | journal = The Journal of Biological Chemistry | volume = 272 | issue = 41 | pages = 25928–34 | date = October 1997 | pmid = 9325326 | doi = 10.1074/jbc.272.41.25928 | s2cid = 38400074 | doi-access = free }} Two of the three proteins, Vma12p and Vma22p, form a complex that binds transiently to Vph1p (subunit a) to aid its assembly and maturation.{{cite journal | vauthors = Hill KJ, Stevens TH | title = Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar H(+)-ATPase complex | journal = The Journal of Biological Chemistry | volume = 270 | issue = 38 | pages = 22329–36 | date = September 1995 | pmid = 7673216 | doi = 10.1074/jbc.270.38.22329 | s2cid = 34639779 | doi-access = free }}{{cite journal | vauthors = Graham LA, Hill KJ, Stevens TH | title = Assembly of the yeast vacuolar H+-ATPase occurs in the endoplasmic reticulum and requires a Vma12p/Vma22p assembly complex | journal = The Journal of Cell Biology | volume = 142 | issue = 1 | pages = 39–49 | date = July 1998 | pmid = 9660861 | pmc = 2133036 | doi = 10.1083/jcb.142.1.39 }}{{cite journal | vauthors = Graham LA, Flannery AR, Stevens TH | title = Structure and assembly of the yeast V-ATPase | journal = Journal of Bioenergetics and Biomembranes | volume = 35 | issue = 4 | pages = 301–12 | date = August 2003 | pmid = 14635776 | doi = 10.1023/A:1025772730586 | s2cid = 37806912 }} Vma21p coordinates assembly of the V_o subunits as well as escorting the V_o domain into vesicles for transport to the Golgi.{{cite journal | vauthors = Malkus P, Graham LA, Stevens TH, Schekman R | title = Role of Vma21p in assembly and transport of the yeast vacuolar ATPase | journal = Molecular Biology of the Cell | volume = 15 | issue = 11 | pages = 5075–91 | date = November 2004 | pmid = 15356264 | pmc = 524777 | doi = 10.1091/mbc.E04-06-0514 }}

The V₁ domain of the V-ATPase is the site of ATP hydrolysis. Unlike V_o, the V₁ domain is hydrophilic. This soluble domain consists of a hexamer of alternating A and B subunits, a central rotor D, peripheral stators G and E, and regulatory subunits C and H. Hydrolysis of ATP drives a conformational change in the six A|B interfaces and with it rotation of the central rotor D. Unlike with the ATP synthase, the V₁ domain is not an active ATPase when dissociated.

V-ATPase (Vacuolar-ATPase) C represents the C terminal subunit that is part of the V1 complex, and is localised to the interface between the V1 and Vo complexes.{{cite journal | vauthors = Inoue T, Forgac M | title = Cysteine-mediated cross-linking indicates that subunit C of the V-ATPase is in close proximity to subunits E and G of the V1 domain and subunit a of the V0 domain | journal = The Journal of Biological Chemistry | volume = 280 | issue = 30 | pages = 27896–903 | date = July 2005 | pmid = 15951435 | doi = 10.1074/jbc.M504890200 | s2cid = 23648833 | doi-access = free }}

The C subunit plays an essential role in controlling the assembly of V-ATPase, acting as a flexible stator that holds together the catalytic (V1) and membrane (VO) sectors of the enzyme .{{cite journal | vauthors = Drory O, Frolow F, Nelson N | title = Crystal structure of yeast V-ATPase subunit C reveals its stator function | journal = EMBO Reports | volume = 5 | issue = 12 | pages = 1148–52 | date = December 2004 | pmid = 15540116 | pmc = 1299189 | doi = 10.1038/sj.embor.7400294 }} The release of subunit C from the ATPase complex results in the dissociation of the V1 and Vo subcomplexes, which is an important mechanism in controlling V-ATPase activity in cells. Essentially, by creating a high electrochemical gradient and low pH, this powers the enzyme to create more ATP.

These related subunits make up the stalk(s) of A/V-ATPase. They are important in assembly, and may function as pushrods in activity. E has a cap to connect to A/B, while G does not.{{cite journal | vauthors = Stewart AG, Laming EM, Sobti M, Stock D | title = Rotary ATPases--dynamic molecular machines | journal = Current Opinion in Structural Biology | volume = 25 | pages = 40–8 | date = April 2014 | pmid = 24878343 | doi = 10.1016/j.sbi.2013.11.013 | doi-access = free }} They likely evolved from a single protein by gene duplication.{{cite journal | vauthors = Imada K, Minamino T, Uchida Y, Kinoshita M, Namba K | title = Insight into the flagella type III export revealed by the complex structure of the type III ATPase and its regulator | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 13 | pages = 3633–8 | date = March 2016 | pmid = 26984495 | doi = 10.1073/pnas.1524025113 | pmc = 4822572 | bibcode = 2016PNAS..113.3633I | doi-access = free }}

{{Main|ATP6V1H}}

Subunit H, is only involved in activity and not in assembly. This subunit also acts as an inhibitor of free V1 subunits; it stops ATP hydrolysis when V1 and Vo are dissociated.{{cite journal | vauthors = Jefferies KC, Forgac M | title = Subunit H of the vacuolar (H+) ATPase inhibits ATP hydrolysis by the free V1 domain by interaction with the rotary subunit F | journal = The Journal of Biological Chemistry | volume = 283 | issue = 8 | pages = 4512–9 | date = February 2008 | pmid = 18156183 | pmc = 2408380 | doi = 10.1074/jbc.M707144200 | doi-access = free }}

The V_o domain is responsible for proton translocation. Unlike the F-type ATP synthase, the V_o domain generally transports protons against their own concentration gradient. Rotation of the V_o domain transports the protons in movement coordinated with the V₁ domain, which is responsible for ATP hydrolysis. The V_o domain is hydrophobic and composed of several dissociable subunits. These subunits are present in the V_o domain to make this a functional proton translocase; they are described below.

The 116kDa subunit (or subunit a) and subunit I are found in the Vo or Ao complex of V- or A-ATPases, respectively. The 116kDa subunit is a transmembrane glycoprotein required for the assembly and proton transport activity of the ATPase complex. Several isoforms of the 116kDa subunit exist, providing a potential role in the differential targeting and regulation of the V-ATPase for specific organelles.

The function of the 116-kDa subunit is not defined, but its predicted structure consists of 6–8 transmembranous sectors, suggesting that it may function similar to subunit a of FO.

Subunit d in V-ATPases, called subunit C in A-ATPases, is a part of the Vo complex. They fit onto the middle of the c ring, so are thought to function as a rotor. There are two versions of this subunit in eukaryotes, d/d1 and d2.

In mammals, d1 (ATP6V0D1) is the ubiquitously expressed version and d2 (ATP6V0D2) is expressed in specific cell types only.{{cite journal | vauthors = Toei M, Saum R, Forgac M | title = Regulation and isoform function of the V-ATPases | journal = Biochemistry | volume = 49 | issue = 23 | pages = 4715–23 | date = June 2010 | pmid = 20450191 | doi = 10.1021/bi100397s | pmc = 2907102 }}

Similar to the F-type ATP synthase, the transmembrane region of the V-ATPase includes a ring of membrane-spanning subunits that are primarily responsible for proton translocation. Dissimilar from the F-type ATP synthase, however, the V-ATPase has multiple related subunits in the c-ring; in fungi such as yeast there are three related subunits (of varied stoichiometry) and in most other eukaryotes there are two.

Yeast V-ATPases fail to assemble when any of the genes that encode subunits are deleted except for subunits H and c".{{cite journal | vauthors = Forgac M | title = The vacuolar H+-ATPase of clathrin-coated vesicles is reversibly inhibited by S-nitrosoglutathione | journal = The Journal of Biological Chemistry | volume = 274 | issue = 3 | pages = 1301–5 | date = January 1999 | pmid = 9880499 | doi = 10.1074/jbc.274.3.1301 | s2cid = 21784089 | doi-access = free }}{{cite journal | vauthors = Whyteside G, Gibson L, Scott M, Finbow ME | title = Assembly of the yeast vacuolar H+-ATPase and ATP hydrolysis occurs in the absence of subunit c" | journal = FEBS Letters | volume = 579 | issue = 14 | pages = 2981–5 | date = June 2005 | pmid = 15907326 | doi = 10.1016/j.febslet.2005.04.049 | s2cid = 32086585 | doi-access = free }}{{cite journal | vauthors = Stevens TH, Forgac M | title = Structure, function and regulation of the vacuolar (H+)-ATPase | journal = Annual Review of Cell and Developmental Biology | volume = 13 | pages = 779–808 | year = 1997 | pmid = 9442887 | doi = 10.1146/annurev.cellbio.13.1.779 }} Without subunit H, the assembled V-ATPase is not active,{{cite journal | vauthors = Parra KJ, Keenan KL, Kane PM | title = The H subunit (Vma13p) of the yeast V-ATPase inhibits the ATPase activity of cytosolic V1 complexes | journal = The Journal of Biological Chemistry | volume = 275 | issue = 28 | pages = 21761–7 | date = July 2000 | pmid = 10781598 | doi = 10.1074/jbc.M002305200 | s2cid = 46127337 | doi-access = free }} and the loss of the c" subunit results in uncoupling of enzymatic activity.

The precise mechanisms by which V-ATPases assembly are still controversial, with evidence suggesting two different possibilities. Mutational analysis and in vitro assays have shown that preassembled V_o and V₁ domains can combine to form one complex in a process called independent assembly. Support for independent assembly includes the findings that the assembled V_o domain can be found at the vacuole in the absence of the V₁ domain, whereas free V₁ domains can be found in the cytoplasm and not at the vacuole.{{cite journal | vauthors = Kane PM | title = Disassembly and reassembly of the yeast vacuolar H(+)-ATPase in vivo | journal = The Journal of Biological Chemistry | volume = 270 | issue = 28 | pages = 17025–32 | date = July 1995 | pmid = 7622524 | doi = 10.1016/S0021-9258(17)46944-4 | doi-access = free }}{{cite journal | vauthors = Sumner JP, Dow JA, Earley FG, Klein U, Jäger D, Wieczorek H | title = Regulation of plasma membrane V-ATPase activity by dissociation of peripheral subunits | journal = The Journal of Biological Chemistry | volume = 270 | issue = 10 | pages = 5649–53 | date = March 1995 | pmid = 7890686 | doi = 10.1074/jbc.270.10.5649 | s2cid = 38963775 | doi-access = free }} In contrast, in vivo pulse-chase experiments have revealed early interactions between V_o and V₁ subunits, to be specific, the a and B subunits, suggesting that subunits are added in a step-wise fashion to form a single complex in a concerted assembly process.{{cite journal | vauthors = Kane PM, Tarsio M, Liu J | title = Early steps in assembly of the yeast vacuolar H+-ATPase | journal = The Journal of Biological Chemistry | volume = 274 | issue = 24 | pages = 17275–83 | date = June 1999 | pmid = 10358087 | doi = 10.1074/jbc.274.24.17275 | s2cid = 42610386 | doi-access = free }}

A relatively new technique called ancestral gene resurrection has shed new light on the evolutionary history of the V-ATPase. It has been shown how the V-ATPase structure of the ancestral form consisting of two different proteins evolves into the fungi version with three different proteins.{{cite web | url = http://blogs.nature.com/news/2012/01/resurrecting-extinct-proteins-shows-how-a-machine-evolves.html | title = Resurrecting extinct proteins shows how a machine evolves | date = 9 January 2012 | first = Helen | last = Pearson | name-list-style = vanc | website = Nature.com News Blog }}{{cite journal | vauthors = Finnigan GC, Hanson-Smith V, Stevens TH, Thornton JW | title = Evolution of increased complexity in a molecular machine | journal = Nature | volume = 481 | issue = 7381 | pages = 360–4 | date = January 2012 | pmid = 22230956 | pmc = 3979732 | doi = 10.1038/nature10724 | bibcode = 2012Natur.481..360F }}[http://uonews.uoregon.edu/content/snapshot-view-v-atpase-molecular-machine-animals-vs-fungi Snapshot view of the V-ATPase molecular machine: animals vs. fungi] {{Webarchive|url=https://web.archive.org/web/20120428023200/http://uonews.uoregon.edu/content/snapshot-view-v-atpase-molecular-machine-animals-vs-fungi |date=2012-04-28 }}, University of Oregon (Accessed 2012-01-11) The V-Type ATPase is similar to the archaeal (so called) A-Type ATP synthase, a fact that supports an archaeal origin of eukaryotes (like Eocyte Hypothesis, see also Lokiarchaeota). The exceptional occurrence of some lineages of archaea with F-type and of some lineages of bacteria with A-type ATPase respectively is regarded as a result of horizontal gene transfer.{{cite journal | vauthors = Hilario E, Gogarten JP | title = Horizontal transfer of ATPase genes--the tree of life becomes a net of life | journal = Bio Systems | volume = 31 | issue = 2–3 | pages = 111–9 | year = 1993 | pmid = 8155843 | doi = 10.1016/0303-2647(93)90038-E | url = http://web.uconn.edu/gogarten/articles/Hilario_Gogarten_Biosys_93.pdf }}

V-ATPases are known to be specifically inhibited by macrolide antibiotics, such as concanamycin (CCA) and balifomycin A1.{{cite journal | vauthors = Bowman EJ, O'Neill FJ, Bowman BJ | title = Mutations of pma-1, the gene encoding the plasma membrane H+-ATPase of Neurospora crassa, suppress inhibition of growth by concanamycin A, a specific inhibitor of vacuolar ATPases | journal = The Journal of Biological Chemistry | volume = 272 | issue = 23 | pages = 14776–86 | date = June 1997 | pmid = 9169444 | doi = 10.1074/jbc.272.23.14776 | s2cid = 29865381 | doi-access = free }} In vivo regulation of V-ATPase activity is accomplished by reversible dissociation of the V₁ domain from the V_o domain. After initial assembly, both the insect Manduca sexta and yeast V-ATPases can reversibly disassemble into free V_o and V₁ domains after a 2- to 5-minute deprivation of glucose. Reversible disassembly may be a general mechanism of regulating V-ATPase activity, since it exists in yeast and insects. Reassembly is proposed to be aided by a complex termed RAVE (regulator of {{chem|H|+}}-ATPase of vacuolar and endosomal membranes).{{cite journal |vauthors=Kane PM, Smardon AM |title=Assembly and regulation of the yeast vacuolar H+-ATPase |journal=Journal of Bioenergetics and Biomembranes |volume=35 |issue=4 |pages=313–21 |date=August 2003 |pmid=14635777 |doi=10.1023/A:1025724814656 |s2cid=7535580 }} Disassembly and reassembly of V-ATPases does not require new protein synthesis but does need an intact microtubular network.{{cite journal |vauthors=Holliday LS, Lu M, Lee BS, Nelson RD, Solivan S, Zhang L, Gluck SL |title=The amino-terminal domain of the B subunit of vacuolar H+-ATPase contains a filamentous actin binding site |journal=The Journal of Biological Chemistry |volume=275 |issue=41 |pages=32331–7 |date=October 2000 |pmid=10915794 |doi=10.1074/jbc.M004795200|s2cid=2601649 |doi-access=free }}

Osteopetrosis is a generic name that represents a group of heritable conditions in which there is a defect in osteoclastic bone resorption. Both dominant and recessive osteopetrosis occur in humans.{{cite journal | vauthors = Michigami T, Kageyama T, Satomura K, Shima M, Yamaoka K, Nakayama M, Ozono K | title = Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis | journal = Bone | volume = 30 | issue = 2 | pages = 436–9 | date = February 2002 | pmid = 11856654 | doi = 10.1016/S8756-3282(01)00684-6 }}{{cite journal | vauthors = Frattini A, Orchard PJ, Sobacchi C, Giliani S, Abinun M, Mattsson JP, Keeling DJ, Andersson AK, Wallbrandt P, Zecca L, Notarangelo LD, Vezzoni P, Villa A | title = Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis | journal = Nature Genetics | volume = 25 | issue = 3 | pages = 343–6 | date = July 2000 | pmid = 10888887 | doi = 10.1038/77131 | s2cid = 21316081 }} Autosomal dominant osteopetrosis shows mild symptoms in adults experiencing frequent bone fractures due to brittle bones. A more severe form of osteopetrosis is termed autosomal recessive infantile malignant osteopetrosis.{{cite journal | vauthors = Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, Babul-Hirji R, Baric I, Canham N, Chitayat D, Dupuis-Girod S, Ellis I, Etzioni A, Fasth A, Fisher A, Gerritsen B, Gulino V, Horwitz E, Klamroth V, Lanino E, Mirolo M, Musio A, Matthijs G, Nonomaya S, Notarangelo LD, Ochs HD, Superti Furga A, Valiaho J, van Hove JL, Vihinen M, Vujic D, Vezzoni P, Villa A | display-authors = 6 | title = The mutational spectrum of human malignant autosomal recessive osteopetrosis | journal = Human Molecular Genetics | volume = 10 | issue = 17 | pages = 1767–73 | date = August 2001 | pmid = 11532986 | doi = 10.1093/hmg/10.17.1767 | doi-access = free }}{{cite journal | vauthors = Fasth A, Porras O | title = Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation | journal = Pediatric Transplantation | volume = 3 | issue = Suppl 1 | pages = 102–7 | year = 1999 | pmid = 10587979 | doi = 10.1034/j.1399-3046.1999.00063.x | s2cid = 31745272 }} Three genes that are responsible for recessive osteopetrosis in humans have been identified. Their products are all directly involved in the proton generation and secretion pathways that are essential for bone resorption. One gene is carbonic anhydrase II (CAII), which, when mutated, causes osteopetrosis with renal tubular acidosis (type 3).{{cite journal | vauthors = Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE | title = Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 9 | pages = 2752–6 | date = May 1983 | pmid = 6405388 | pmc = 393906 | doi = 10.1073/pnas.80.9.2752 | bibcode = 1983PNAS...80.2752S | doi-access = free }} Mutations to the chloride channel CLC-7 gene also lead to both dominant and recessive osteopetrosis.{{cite journal | vauthors = Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A | title = Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis | journal = Journal of Bone and Mineral Research | volume = 18 | issue = 10 | pages = 1740–7 | date = October 2003 | pmid = 14584882 | doi = 10.1359/jbmr.2003.18.10.1740 | s2cid = 20966489 | doi-access = free }} Approximately 50% of patients with recessive infantile malignant osteopetrosis have mutations to the a3 subunit isoform of V-ATPase.{{cite journal | vauthors = Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C | title = Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis | journal = Human Molecular Genetics | volume = 9 | issue = 13 | pages = 2059–63 | date = August 2000 | pmid = 10942435 | doi = 10.1093/hmg/9.13.2059 | doi-access = free }} In humans, 26 mutations have been identified in V-ATPase subunit isoform a3, found in osteoclasts, that result in the bone disease autosomal recessive osteopetrosis.{{cite journal | vauthors = Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F | title = TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA | journal = Human Mutation | volume = 24 | issue = 3 | pages = 225–35 | date = September 2004 | pmid = 15300850 | doi = 10.1002/humu.20076 | s2cid = 31788054 | doi-access = free }}

The importance of V-ATPase activity in renal proton secretion is highlighted by the inherited disease distal renal tubular acidosis. In all cases, renal tubular acidosis results from a failure of the normal renal mechanisms that regulate systemic pH. There are four types of renal tubular acidosis. Type 1 is distal renal tubular acidosis and results from a failure of the cortical collecting duct to acidify the urine below pH 5.{{cite journal | vauthors = Alper SL | title = Genetic diseases of acid-base transporters | journal = Annual Review of Physiology | volume = 64 | pages = 899–923 | year = 2002 | pmid = 11826292 | doi = 10.1146/annurev.physiol.64.092801.141759 }} Some patients with autosomal recessive dRTA also have sensorineural hearing loss.{{cite journal | vauthors = Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, Rodriguez-Soriano J, Santos F, Cremers CW, Di Pietro A, Hoffbrand BI, Winiarski J, Bakkaloglu A, Ozen S, Dusunsel R, Goodyer P, Hulton SA, Wu DK, Skvorak AB, Morton CC, Cunningham MJ, Jha V, Lifton RP | display-authors = 6 | title = Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness | journal = Nature Genetics | volume = 21 | issue = 1 | pages = 84–90 | date = January 1999 | pmid = 9916796 | doi = 10.1038/5022 | s2cid = 34262548 }} Inheritance of this type of RTA results from either mutations to V-ATPase subunit isoform B1 or isoform a4 or mutations of band 3 (also called AE1), a Cl-/HCO3- exchanger.{{cite journal | vauthors = Karet FE, Gainza FJ, Györy AZ, Unwin RJ, Wrong O, Tanner MJ, Nayir A, Alpay H, Santos F, Hulton SA, Bakkaloglu A, Ozen S, Cunningham MJ, di Pietro A, Walker WG, Lifton RP | display-authors = 6 | title = Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 11 | pages = 6337–42 | date = May 1998 | pmid = 9600966 | pmc = 27686 | doi = 10.1073/pnas.95.11.6337 | bibcode = 1998PNAS...95.6337K | doi-access = free }}{{cite journal | vauthors = Stehberger PA, Schulz N, Finberg KE, Karet FE, Giebisch G, Lifton RP, Geibel JP, Wagner CA | title = Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis | journal = Journal of the American Society of Nephrology | volume = 14 | issue = 12 | pages = 3027–38 | date = December 2003 | pmid = 14638902 | doi = 10.1097/01.ASN.0000099375.74789.AB | doi-access = free }} Twelve different mutations to V-ATPase isoform B1{{cite journal | vauthors = 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 | display-authors = 6 | title = Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss | journal = Journal of Medical Genetics | volume = 39 | issue = 11 | pages = 796–803 | date = November 2002 | pmid = 12414817 | pmc = 1735017 | doi = 10.1136/jmg.39.11.796 }} and twenty-four different mutations in a4 lead to dRTA. Reverse transcription polymerase chain reaction studies have shown expression of the a4 subunit in the intercalated cell of the kidney and in the cochlea. dRTA caused by mutations in the a4 subunit gene in some cases can be associated with deafness due to a failure to normally acidify the endolymph of the inner ear.

X-linked myopathy with excessive autophagy is a rare genetic disease resulting from mutations in the VMA21 gene.{{cite journal | vauthors = Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, Naranian T, Paroutis P, Guo R, Ren ZP, Nishino I, Chabrol B, Pellissier JF, Minetti C, Udd B, Fardeau M, Tailor CS, Mahuran DJ, Kissel JT, Kalimo H, Levy N, Manolson MF, Ackerley CA, Minassian BA | display-authors = 6 | title = VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy | journal = Acta Neuropathologica | volume = 125 | issue = 3 | pages = 439–57 | date = March 2013 | pmid = 23315026 | doi = 10.1007/s00401-012-1073-6 | s2cid = 20528180 }} The disease has a childhood onset and results in a slowly progressive muscle weakness, typically beginning in the legs, and some patients can eventually require wheelchair assistance with advanced age. The Vma21 protein assists in assembly of the V-ATPase, and XMEA-associated mutations result in decreased activity of the V-ATPase and increased lysosomal pH.

The term V_o has a lowercase letter "o" (not the number "zero") in subscript. The "o" stands for oligomycin, which binds to the homologous region in F-ATPase. It is worth noting that the human gene notations at NCBI designate it as "zero" rather than the letter "o". For example, the gene for the human c subunit of Vo is listed in NCBI gene database as "ATP6V0C" (with a zero), rather than "ATP6VOC" (with an "o"). Many pieces of literature make this mistake as well.

• ATP synthase
• F-ATPase
• Na+/K+-ATPase
• P-type ATPase

{{Reflist|32em}}

• {{MeshName|V-Type+ATPase}}

{{Ion pumps}}

{{Proton pumps}}

{{DEFAULTSORT:V-Atpase}}

Category:Enzymes

Category:Transport proteins

Category:Transmembrane proteins