View source for Biology:V-ATPase

{{Short description|Family of transport protein complexes}}
{{Pfam box
|Symbol=V-ATPase
|image=VATPase-en.png|caption=V-ATPase schematic
|TCDB=3.A.2
| OPM family= 5
| OPM protein= 2bl2
| Membranome superfamily = 226
}}
{{Pfam_box
| Symbol = ATP-synt_C
| Name = V-ATPase, subunit c (Vo)
| image =2bl2.png
| width =250
| caption =Membrane-spanning region of the V-type sodium [[Biology:ATPase|ATPase]] from ''[[Biology:Enterococcus hirae|Enterococcus hirae]]''. Calculated hydrocarbon boundaries of the [[Biology:Lipid bilayer|lipid bilayer]] are shown by red and blue dots
| Pfam= PF00137
| InterPro= IPR002379
| SMART=
| Prosite = PDOC00526
| SCOP = 1aty
| TCDB =
| PDB=
}}
{{Infobox protein family
| Symbol = V-ATPase_C
| Name = V-ATPase, subunit C (V1)
| image = PDB 1u7l EBI.jpg
| width = 
| caption = crystal structure of subunit C (vma5p) of the yeast v-atpase
| Pfam = PF03223
| Pfam_clan =  
| InterPro = IPR004907
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1u7l
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = V_ATPase_I
| Name = V-ATPase, subunit I/a
| image = 
| width = 
| caption = structure of a peptide derived from h+-v-atpase subunit a
| Pfam = PF01496
| Pfam_clan =  
| InterPro = IPR002490
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 3rrk
| TCDB = 3.A.2
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = vATP-synt_E
| Name =  V-ATPase, subunit E
| image = 
| width = 
| caption = crystal structure of ph1978 from pyrococcus horikoshii ot3 (form ii)
| Pfam = PF01991
| Pfam_clan = CL0255
| InterPro = IPR002842
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = vATP-synt_AC39
| Name =  V-ATPase, subunit d/d2
| image = PDB 1r5z EBI.jpg
| width = 
| caption = crystal structure of subunit C (yeast subunit d) of v-atpase
| Pfam = PF01992
| Pfam_clan =  
| InterPro = IPR002843
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1r5z
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = V-ATPase_H_N
| Name = V-ATPase, subunit H, N-terminal
| image = PDB 1ho8 EBI.jpg
| width = 
| caption = crystal structure of the regulatory subunit H of the v-type atpase of saccharomyces cerevisiae
| Pfam = PF03224
| Pfam_clan = CL0020
| InterPro = IPR004908
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 1ho8
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}
{{Infobox protein family
| Symbol = V-ATPase_G
| Name = V-ATPase, subunit G
| image = 
| width = 
| caption = association of subunit d (vma6p) and e (vma4p) with g (vma10p) and the nmr solution structure of subunit g (g1-59) of the saccharomyces cerevisiae v1vo atpase
| Pfam = PF03179
| Pfam_clan = CL0255
| InterPro = IPR005124
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
}}

'''Vacuolar-type ATPase''' ('''V-ATPase''') is a highly conserved evolutionarily ancient [[Biology:Enzyme|enzyme]] with remarkably diverse functions in [[Biology:Eukaryote|eukaryotic]] organisms.<ref>{{cite journal | vauthors = Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H | title = The cellular biology of proton-motive force generation by V-ATPases | journal = The Journal of Experimental Biology | volume = 203 | issue = Pt 1 | pages = 89–95 | date = January 2000 | doi = 10.1242/jeb.203.1.89 | pmid = 10600677 | url = http://jeb.biologists.org/cgi/reprint/203/1/89 }}</ref> V-ATPases acidify a wide array of intracellular organelles and [[Physics:Proton pump|pumps protons]] across the [[Biology:Cell membrane|plasma membranes]] of numerous cell types. V-ATPases couple the energy of [[Biology:ATP hydrolysis|ATP hydrolysis]] to proton [[Biology:Transport protein|transport]] across intracellular and plasma membranes of eukaryotic cells. It is generally seen as the polar opposite of [[Biology:ATP synthase|ATP synthase]] because ATP synthase is a proton channel that uses the energy from a proton gradient to produce ATP. V-ATPase however, is a proton pump that uses the energy from ATP hydrolysis to produce a proton gradient.

The '''Archaea-type ATPase''' ('''A-ATPase''') is a related group of [[Biology:ATPase|ATPase]]s found in [[Biology:Archaea|archaea]] that often work as an [[Biology:ATP synthase|ATP synthase]]. It forms a clade '''V/A-ATPase''' with V-ATPase. Most members of either group shuttle protons ({{chem|H|+}}), but a few members have evolved to use sodium ions ({{chem|Na|+}}) instead.
{{TOC level|4}}

==Roles played by V-ATPases==

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.<ref name = "Ohya_1991">{{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 }}</ref> In synaptic transmission in neuronal cells, V-ATPase acidifies synaptic vesicles.<ref>{{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 }}</ref> [[Biology:Norepinephrine|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, [[Biology:Spermatozoon|sperm]], midgut cells of [[Biology:Insect|insect]]s, and certain tumor cells.<ref>{{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 }}</ref> Plasma membrane V-ATPases are involved in processes such as [[Chemistry:PH|pH]] [[Homeostasis|homeostasis]], coupled transport, and tumor [[Medicine:Metastasis|metastasis]]. V-ATPases in the acrosomal membrane of sperm acidify the [[Medicine:Acrosome|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 [[Biology:Urine|urine]], allowing for [[Chemistry:Bicarbonate|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.<ref name=":0">{{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 }}</ref>

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. <ref>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.</ref>

== Structure ==
{{split|V/A-ATPase subunit C|V/A-ATPase subunits E and G|V/A-ATPase subunit H|V/A-ATPase subunit d/C|date=September 2020|section=y}}<!-- Not a lot we can write right now, but the Pfam boxes are simultaneously messy and incomplete... -->
The [[Biology:Yeast|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<sub>o</sub> domain (membrane associated subunits, lowercase letters on the figure) or the V<sub>1</sub> domain (peripherally associated subunits, uppercase letters on the figure).

The V<sub>1</sub> 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 V<sub>1</sub> domain also contains the subunits D and F, which form a central rotor axle.<ref name = "Kitagawa_2008">{{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 }}</ref> The V<sub>1</sub> 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<sub>o</sub> 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 (''[[Biology:Manduca sexta|Manduca sexta]]'') V-ATPase. The mammalian V<sub>o</sub> 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 [[Medicine:Osteopetrosis|osteopetrosis]], and mutations to the a4 isoform result in distal renal tubular acidosis, in some cases with sensorineural deafness.

The V<sub>1</sub> domain is responsible for ATP hydrolysis, whereas the V<sub>o</sub> 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.<ref name = "Muench_2009">{{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 }}</ref><ref name = "Diepholz_2008">{{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 }}</ref><ref name = "Zhang_2008">{{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 }}</ref> 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 V<sub>1</sub> and V<sub>o</sub> 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 [[Chemistry:Stoichiometry|stoichiometry]] of two protons translocated for each ATP hydrolyzed has been proposed by Johnson.<ref name = "Johnson_1982">{{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 }}</ref>

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<sub>o</sub> domain assembly and are termed Vma12p, Vma21p, and Vma22p.<ref name = "Hirata_1993">{{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 }}</ref><ref name = "Ho_1993">{{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 }}</ref><ref name = "Hill_1994">{{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 }}</ref><ref name = "Jackson_1997">{{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 }}</ref> Two of the three proteins, Vma12p and Vma22p, form a complex that binds transiently to Vph1p (subunit a) to aid its assembly and maturation.<ref name = "Hill_1994" /><ref name = "Hill_1995">{{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 }}</ref><ref name = "Graham_19989">{{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 }}</ref><ref name = "Graham_2003">{{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 }}</ref> Vma21p coordinates assembly of the V<sub>o</sub> subunits as well as escorting the V<sub>o</sub> domain into vesicles for transport to the [[Biology:Golgi apparatus|Golgi]].<ref = "Malkus_2004">{{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 }}</ref>

===V<sub>1</sub>===

The V<sub>1</sub> domain of the V-ATPase is the site of ATP hydrolysis.  Unlike V<sub>o</sub>, the V<sub>1</sub> domain is hydrophilic.<ref name=":0" /> 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 V<sub>1</sub> domain is not an active ATPase when dissociated.

{| class="wikitable"
|+ V<sub>1</sub> Subunits<ref name=pmid24878343/>
|-
! Subunit !! Human Gene !! Note
|-
| style="text-align:center" | A, B || ATP6V1A, ATP6V1B1, [[Biology:ATP6V1B2|ATP6V1B2]] || Catalytic hexamer.
|-
| style="text-align:center" | C || ATP6V1C1, ATP6V1C2 ||
|-
| style="text-align:center" | D || [[Biology:ATP6V1D|ATP6V1D]] || Central rotor stalk, responsible for ion specificity.
|-
| style="text-align:center" | E, G || [[Biology:ATP6V1E1|ATP6V1E1]], ATP6V1E2, ATP6V1G1, [[Biology:ATP6V1G2|ATP6V1G2]], ATP6V1G3 ||
|-
| style="text-align:center" | F || ATP6V1F ||
|-
| style="text-align:center" | H || ATP6V1H ||
|}

====Subunit C====

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.<ref name="pmid15951435">{{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 }}</ref>

=====Subunit C function=====
The C subunit plays an essential role in controlling the assembly of V-ATPase, acting as a flexible stator that holds together the [[Biology:Biocatalysis|catalytic]] (V1) and [[Chemistry:Membrane|membrane]] (VO) sectors of the enzyme .<ref name="pmid15540116">{{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 }}</ref> The release of subunit C from the ATPase complex results in the [[Chemistry:Dissociation|dissociation]] of the V1 and Vo subcomplexes, which is an important [[Biology:Nuclear receptor#Mechanism of action|mechanism]] in controlling V-ATPase activity in [[Biology:Cell|cells]]. Essentially, by creating a high electrochemical gradient and low pH, this powers the enzyme to create more ATP.

====Subunits E, G====
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.<ref name=pmid24878343>{{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 }}</ref> They likely evolved from a single protein by [[Biology:Gene duplication|gene duplication]].<ref>{{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 }}</ref> 

====Subunit H====
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.<ref name="Jefferies_2008">{{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 }}</ref>

===V<sub>o</sub>===
The V<sub>o</sub> domain is responsible for proton translocation.  Unlike the F-type [[Biology:ATP synthase|ATP synthase]], the V<sub>o</sub> domain generally transports protons against their own concentration gradient.  Rotation of the V<sub>o</sub> domain transports the protons in movement coordinated with the V<sub>1</sub> domain, which is responsible for ATP hydrolysis. The V<sub>o</sub> domain is hydrophobic and composed of several dissociable subunits.<ref name=":0" /> These subunits are present in the V<sub>o</sub> domain to make this a functional proton translocase; they are described below.

{| class="wikitable"
|+ V<sub>o</sub> Subunits<ref name=pmid24878343/>
|-
! Subunit !! Human Gene !! Note
|-
| style="text-align:center" |a/I || ATP6V0A1, ATP6V0A2, ATP6V0A4|| 
|-
| style="text-align:center" |[[Biology:ATP synthase subunit C|c]] || [[Biology:ATP6V0B|ATP6V0B]], ATP6V0C|| Ring of varied size.
|-
| style="text-align:center" |d/C || ATP6V0D1, [[Biology:ATP6V0D2|ATP6V0D2]]||
|-
| style="text-align:center" |e || ATP6V0E1, ATP6V0E2|| 9 kDa hydrophobic assembly protein.
|-
| style="text-align:center" |AC45/S1 || [[Biology:ATP6AP1|ATP6AP1]] || Accessory subunit
|-
|style="text-align:center" |  S2 || ATP6AP2 || Accessory subunit
|}

====Subunit a/I====
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 [[Biology:Transmembrane protein|transmembrane]] [[Chemistry:Glycoprotein|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/C====
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.<ref name="pmid20450191"/>

In mammals, d1 (ATP6V0D1) is the ubiquitously expressed version and d2 ([[Biology:ATP6V0D2|ATP6V0D2]]) is expressed in specific cell types only.<ref name="pmid20450191">{{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 }}</ref>

====Subunit c====
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.

==V-ATPase assembly==

Yeast V-ATPases fail to assemble when any of the genes that encode subunits are deleted except for subunits H and c".<ref name ="Forgac_1999">{{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 }}</ref><ref name = "Whyteside_2005">{{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 }}</ref><ref name = "Stevens_1997">{{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 }}</ref> Without subunit H, the assembled V-ATPase is not active,<ref name = "Ho_1993" /><ref name = "Parra_2000">{{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 }}</ref> and the loss of the c" subunit results in uncoupling of enzymatic activity.<ref name = "Whyteside_2005" />

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<sub>o</sub> and V<sub>1</sub> domains can combine to form one complex in a process called independent assembly. Support for independent assembly includes the findings that the assembled V<sub>o</sub> domain can be found at the vacuole in the absence of the V<sub>1</sub> domain, whereas free V<sub>1</sub> domains can be found in the [[Biology:Cytoplasm|cytoplasm]] and not at the [[Biology:Vacuole|vacuole]].<ref name = "Kane_1995">{{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 }}</ref><ref name = "Sumner_1995">{{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 }}</ref> In contrast, ''in vivo'' pulse-chase experiments have revealed early interactions between V<sub>o</sub> and V<sub>1</sub> 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.<ref name = "Kane_1999">{{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 }}</ref>

==V-ATPase evolution==
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.<ref name="evo1">{{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 }}</ref><ref name="evo2">{{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 }}</ref><ref name="evo3">[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)</ref> 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 [[Biology:Thermoproteota#Eocyte hypothesis|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 [[Biology:Horizontal gene transfer|horizontal gene transfer]].<ref name="Hilario_Gogarten">{{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 }}</ref>

==Regulation of V-ATPase activity==

V-ATPases are known to be specifically inhibited by macrolide antibiotics, such as concanamycin (CCA) and balifomycin A<small>1</small>.<ref name="Bowman_1997">{{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 }}</ref> ''In vivo'' regulation of V-ATPase activity is accomplished by reversible dissociation of the V<sub>1</sub> domain from the V<sub>o</sub> domain. After initial assembly, both the insect ''[[Biology:Manduca sexta|Manduca sexta]]'' and yeast V-ATPases can reversibly disassemble into free V<sub>o</sub> and V<sub>1</sub> domains after a 2- to 5-minute deprivation of glucose.<ref name="Kane_1995" /> 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).<ref name="Kane_2003">{{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 }}</ref> Disassembly and reassembly of V-ATPases does not require new protein synthesis but does need an intact [[Biology:Microtubule|microtubular]] network.<ref name="Holliday_2000">{{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 }}</ref>

==Human diseases==

===Osteopetrosis===

[[Medicine:Osteopetrosis|Osteopetrosis]] is generic name that represents a group of heritable conditions in which there is a defect in [[Biology:Osteoclast|osteoclastic bone resorption]]. Both dominant and recessive osteopetrosis occur in humans.<ref name = "Michigami_2002">{{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 }}</ref><ref name = "Frattini_2000">{{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 }}</ref> Autosomal dominant osteopetrosis shows mild symptoms in adults experiencing frequent bone fractures due to brittle bones.<ref name = "Michigami_2002" /> A more severe form of osteopetrosis is termed autosomal recessive infantile malignant osteopetrosis.<ref name = "Frattini_2000" /><ref name = "Sobacchi_2001">{{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 }}</ref><ref name = "Fasth_1999">{{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 }}</ref> Three genes that are responsible for recessive osteopetrosis in humans have been identified. They are all directly involved in the proton generation and secretion pathways that are essential for bone resorption. One gene is [[Biology:Carbonic anhydrase|carbonic anhydrase]] II (CAII), which, when mutated, causes osteopetrosis with [[Medicine:Renal tubular acidosis|renal tubular acidosis]](type 3).<ref name = "Sly_1983">{{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 }}</ref> Mutations to the chloride channel ClC7 gene also lead to both dominant and recessive osteopetrosis.<ref name = "Michigami_2002" /> Approximately 50% of patients with recessive infantile malignant osteopetrosis have mutations to the a3 subunit isoform of V-ATPase.<ref name = "Sobacchi_2001" /> <ref name = "Kornak_2000">{{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 }}</ref><ref name = "Frattini_2003">{{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 }}</ref> 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.<ref name = "Sobacchi_2001" /><ref name = "Frattini_2000" /><ref name = "Kornak_2000" /><ref name = "Susani_2004">{{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 }}</ref>

===Distal renal tubular acidosis (dRTA)===

The importance of V-ATPase activity in renal proton secretion is highlighted by the inherited disease distal [[Medicine:Renal tubular acidosis|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.<ref name = "Alper_2002">{{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 }}</ref> Some patients with autosomal recessive dRTA also have sensorineural hearing loss.<ref name = "Karet_1999">{{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 }}</ref> Inheritance of this type of RTA results from either mutations to V-ATPase subunit isoform B1 or isoform a4 or mutations of [[Biology:Band 3|band 3]] (also called AE1), a Cl-/HCO3- exchanger.<ref name = "Karet_1999" /><ref name = "Karet_1998">{{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 }}</ref><ref name = "Stehberger_2003">{{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 }}</ref> Twelve different mutations to V-ATPase isoform B1<ref name = "Stover_2002">{{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 }}</ref> and twenty-four different mutations in a4 lead to dRTA.<ref name = "Stover_2002" /><ref name = "Karet_1999" /> Reverse transcription [[Biology:Polymerase chain reaction|polymerase chain reaction]] studies have shown expression of the a4 subunit in the intercalated cell of the kidney and in the [[Medicine:Cochlea|cochlea]].<ref name = "Stover_2002" /> 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 [[Biology:Endolymph|endolymph]] of the inner ear.<ref name = "Stehberger_2003" />

===X-linked myopathy with excessive autophagy (XMEA)===

X-linked myopathy with excessive autophagy is a rare genetic disease resulting from mutations in the VMA21 gene.<ref name="VMA21">{{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 }}</ref>  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.<ref name="VMA21" />

==Nomenclature==

The term V<sub>o</sub> has a lowercase letter "o" (not the number "zero") in subscript. The "o" stands for [[Chemistry:Oligomycin|oligomycin]], which binds to the homologous region in [[Biology:F-ATPase|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.

== See also ==
*[[Biology:ATP synthase|ATP synthase]]
*[[Biology:F-ATPase|F-ATPase]]
*Na+/K+-ATPase

== References ==
{{Reflist|32em}}

== External links ==
* {{MeshName|V-Type+ATPase}}

{{Ion pumps}}
{{Proton pumps}}

{{DEFAULTSORT:V-Atpase}}
[[Category:Enzymes]]
[[Category:Transport proteins]]
[[Category:Transmembrane proteins]]

{{Sourceattribution|V-ATPase}}