Summary: V-type ATPase 116kDa subunit family
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "V-ATPase". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
V-ATPase Edit Wikipedia article
crystal structure of subunit C (vma5p) of the yeast v-atpase
crystal structure of subunit C (yeast subunit d) of v-atpase
crystal structure of the regulatory subunit H of the v-type atpase of saccharomyces cerevisiae
-ATPase (V-ATPase) is a highly conserved evolutionarily ancient enzyme with remarkably diverse functions in eukaryotic organisms. V-ATPases acidify a wide array of intracellular organelles and pump protons across the plasma membranes of numerous cell types. V-ATPases couple the energy of ATP hydrolysis to proton transport across intracellular and plasma membranes of eukaryotic cells. It is generally seen as the polar opposite of 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.
- 1 Roles played by V-ATPases
- 2 Structure
- 3 V-ATPase assembly
- 4 V-ATPase evolution
- 5 Regulation of V-ATPase activity
- 6 Human diseases
- 7 Nomenclature
- 8 See also
- 9 References
- 10 External links
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 H+
antiporter system. In synaptic transmission in neuronal cells, V-ATPase acidifies synaptic vesicles. Norepinephrine enters vesicles by V-ATPase.
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. 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.
The yeast V-ATPase is the best characterized. There are at least 13 subunits identified to form a functional V-ATPase complex, which consists of two domains. The subunits belong to either the Vo domain (membrane associated subunits, lowercase letters on the figure) or the V1 domain (peripherally associated subunits, uppercase letters on the figure).
The V1 includes 8 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. 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 Vo domain contains 6 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 Vo 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 Vo 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. 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 V0 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.
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 Vo domain assembly and are termed Vma12p, Vma21p, and Vma22p. Two of the three proteins, Vma12p and Vma22p, form a complex that binds transiently to Vph1p (subunit a) to aid its assembly and maturation. Vma21p coordinates assembly of the Vo subunits as well as escorting the Vo domain into vesicles for transport to the Golgi.
The V1 domain of the V-ATPase is the site of ATP hydrolysis. 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.
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 catalytic (V1) and membrane (V0) sectors of the enzyme . The release of subunit C from the ATPase complex results in the dissociation of the V1 and V0 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.
This subunit, is part of V1, and is important in V-ATPase assembly and activity.
This subunit is only involved in activity and not in assembly.
The Vo domain is responsible for proton translocation. Opposite the F-type ATP synthase, the Vo domain is transporting protons against their own concentration gradient. Rotation of the Vo domain transports the protons in movement coordinated with the V1 domain, which is responsible for ATP hydrolysis. Several subunits are present in the Vo domain to make this a functional proton translocase; they are described below.
In molecular biology, 116kDa subunit (or subunit a) and subunit I are found in the V0 or A0 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.
Subunit I function
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.
This particular subunit is a non-integral membrane component of the membrane pore domain and is required for proper assembly of the V0 sector. It is thought to be involved in the regulated assembly of V1 subunits onto the membrane sector or alternatively may prevent the passage of protons through V0 pores.
This subunit is part of the integral membrane V0 complex of vacuolar ATPase, which is responsible for acidifying intracellular compartments in eukaryotic cells. Therefore, they help provide most of the energy required for transport processes in the vacuolar system. They are thought to play a role in coupling of proton transport and ATP hydrolysis and aid the regulation of osteoclast fusion and bone formation.
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". Without subunit H, the assembled V-ATPase is not active. 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 Vo 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 Vo 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. In contrast, in vivo pulse-chase experiments have revealed early interactions between Vo 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.
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. 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 exceptionally 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.
Regulation of V-ATPase activity
In vivo regulation of V-ATPase activity is accomplished by reversible dissociation of the V1 domain from the Vo domain. After initial assembly, both the insect Manduca sexta and yeast V-ATPases can reversibly disassemble into free Vo 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 H+
-ATPase of vacuolar and endosomal membranes). Dissasembly and reassembly of V-ATPases does not require new protein synthesis but does need an intact microtubular network.
Osteopetrosis is 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. 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. 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 carbonic anhydrase II (CAII), which, when mutated, causes osteopetrosis with renal tubular acidosis(type 3). Mutations to the chloride channel ClC7 gene also lead to both dominant and recessive osteopetrosis. Approximately 50% of patients with recessive infantile malignant osteopetrosis have mutations to the a3 subunit isoform of V-ATPase.  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.
Distal renal tubular acidosis (dRTA)
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. Some patients with autosomal recessive dRTA also have sensorineural hearing loss. 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. Twelve different mutations to V-ATPase isoform B1 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. 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 Vo has a lowercase letter "o" (not the number "zero") in subscript. The "o" stands for oligomycin. 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").
- Nelson N, Perzov N, Cohen A, Hagai K, Padler V, Nelson H (January 2000). "The cellular biology of proton-motive force generation by V-ATPases". The Journal of Experimental Biology. 203 (Pt 1): 89–95. PMID 10600677.
- Ohya Y, Umemoto N, Tanida I, Ohta A, Iida H, Anraku Y (July 1991). "Calcium-sensitive cls mutants of Saccharomyces cerevisiae showing a Pet- phenotype are ascribable to defects of vacuolar membrane H(+)-ATPase activity". The Journal of Biological Chemistry. 266 (21): 13971–7. PMID 1830311.
- Wienisch M, Klingauf J (August 2006). "Vesicular proteins exocytosed and subsequently retrieved by compensatory endocytosis are nonidentical". Nature Neuroscience. 9 (8): 1019–27. doi:10.1038/nn1739. PMID 16845386.
- Izumi H, Torigoe T, Ishiguchi H, Uramoto H, Yoshida Y, Tanabe M, Ise T, Murakami T, Yoshida T, Nomoto M, Kohno K (December 2003). "Cellular pH regulators: potentially promising molecular targets for cancer chemotherapy". Cancer Treatment Reviews. 29 (6): 541–9. doi:10.1016/S0305-7372(03)00106-3. PMID 14585264.
- Kitagawa N, Mazon H, Heck AJ, Wilkens S (February 2008). "Stoichiometry of the peripheral stalk subunits E and G of yeast V1-ATPase determined by mass spectrometry". The Journal of Biological Chemistry. 283 (6): 3329–37. doi:10.1074/jbc.M707924200. PMID 18055462.
- Muench SP, Huss M, Song CF, Phillips C, Wieczorek H, Trinick J, Harrison MA (March 2009). "Cryo-electron microscopy of the vacuolar ATPase motor reveals its mechanical and regulatory complexity". Journal of Molecular Biology. 386 (4): 989–99. doi:10.1016/j.jmb.2009.01.014. PMID 19244615.
- Diepholz M, Börsch M, Böttcher B (October 2008). "Structural organization of the V-ATPase and its implications for regulatory assembly and disassembly". Biochemical Society Transactions. 36 (Pt 5): 1027–31. doi:10.1042/BST0361027. PMID 18793183.
- Zhang Z, Zheng Y, Mazon H, Milgrom E, Kitagawa N, Kish-Trier E, Heck AJ, Kane PM, Wilkens S (December 2008). "Structure of the yeast vacuolar ATPase". The Journal of Biological Chemistry. 283 (51): 35983–95. doi:10.1074/jbc.M805345200. PMC . PMID 18955482.
- Johnson RG, Beers MF, Scarpa A (September 1982). "H+ ATPase of chromaffin granules. Kinetics, regulation, and stoichiometry". The Journal of Biological Chemistry. 257 (18): 10701–7. PMID 6213624.
- Hirata R, Umemoto N, Ho MN, Ohya Y, Stevens TH, Anraku Y (January 1993). "VMA12 is essential for assembly of the vacuolar H(+)-ATPase subunits onto the vacuolar membrane in Saccharomyces cerevisiae". The Journal of Biological Chemistry. 268 (2): 961–7. PMID 8419376.
- Ho MN, Hirata R, Umemoto N, Ohya Y, Takatsuki A, Stevens TH, Anraku Y (August 1993). "VMA13 encodes a 54-kDa vacuolar H(+)-ATPase subunit required for activity but not assembly of the enzyme complex in Saccharomyces cerevisiae". The Journal of Biological Chemistry. 268 (24): 18286–92. PMID 8349704.
- Hill KJ, Stevens TH (September 1994). "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". Molecular Biology of the Cell. 5 (9): 1039–50. doi:10.1091/mbc.5.9.1039. PMC . PMID 7841520.
- Jackson DD, Stevens TH (October 1997). "VMA12 encodes a yeast endoplasmic reticulum protein required for vacuolar H+-ATPase assembly". The Journal of Biological Chemistry. 272 (41): 25928–34. doi:10.1074/jbc.272.41.25928. PMID 9325326.
- Hill KJ, Stevens TH (September 1995). "Vma22p is a novel endoplasmic reticulum-associated protein required for assembly of the yeast vacuolar H(+)-ATPase complex". The Journal of Biological Chemistry. 270 (38): 22329–36. doi:10.1074/jbc.270.38.22329. PMID 7673216.
- Graham LA, Hill KJ, Stevens TH (July 1998). "Assembly of the yeast vacuolar H+-ATPase occurs in the endoplasmic reticulum and requires a Vma12p/Vma22p assembly complex". The Journal of Cell Biology. 142 (1): 39–49. doi:10.1083/jcb.142.1.39. PMC . PMID 9660861.
- Graham LA, Flannery AR, Stevens TH (August 2003). "Structure and assembly of the yeast V-ATPase". Journal of Bioenergetics and Biomembranes. 35 (4): 301–12. doi:10.1023/A:1025772730586. PMID 14635776.
- Malkus P, Graham LA, Stevens TH, Schekman R (November 2004). "Role of Vma21p in assembly and transport of the yeast vacuolar ATPase". Molecular Biology of the Cell. 15 (11): 5075–91. doi:10.1091/mbc.E04-06-0514. PMC . PMID 15356264.
- Inoue T, Forgac M (July 2005). "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". The Journal of Biological Chemistry. 280 (30): 27896–903. doi:10.1074/jbc.M504890200. PMID 15951435.
- Drory O, Frolow F, Nelson N (December 2004). "Crystal structure of yeast V-ATPase subunit C reveals its stator function". EMBO Reports. 5 (12): 1148–52. doi:10.1038/sj.embor.7400294. PMC . PMID 15540116.
- Forgac M (January 1999). "The vacuolar H+-ATPase of clathrin-coated vesicles is reversibly inhibited by S-nitrosoglutathione". The Journal of Biological Chemistry. 274 (3): 1301–5. doi:10.1074/jbc.274.3.1301. PMID 9880499.
- Whyteside G, Gibson L, Scott M, Finbow ME (June 2005). "Assembly of the yeast vacuolar H+-ATPase and ATP hydrolysis occurs in the absence of subunit c". FEBS Letters. 579 (14): 2981–5. doi:10.1016/j.febslet.2005.04.049. PMID 15907326.
- Stevens TH, Forgac M (1997). "Structure, function and regulation of the vacuolar (H+)-ATPase". Annual Review of Cell and Developmental Biology. 13: 779–808. doi:10.1146/annurev.cellbio.13.1.779. PMID 9442887.
- Parra KJ, Keenan KL, Kane PM (July 2000). "The H subunit (Vma13p) of the yeast V-ATPase inhibits the ATPase activity of cytosolic V1 complexes". The Journal of Biological Chemistry. 275 (28): 21761–7. doi:10.1074/jbc.M002305200. PMID 10781598.
- Kane PM (July 1995). "Disassembly and reassembly of the yeast vacuolar H(+)-ATPase in vivo". The Journal of Biological Chemistry. 270 (28): 17025–32. doi:10.1074/jbc.270.28.17025 (inactive 2017-01-15). PMID 7622524.
- Sumner JP, Dow JA, Earley FG, Klein U, Jäger D, Wieczorek H (March 1995). "Regulation of plasma membrane V-ATPase activity by dissociation of peripheral subunits". The Journal of Biological Chemistry. 270 (10): 5649–53. doi:10.1074/jbc.270.10.5649. PMID 7890686.
- Kane PM, Tarsio M, Liu J (June 1999). "Early steps in assembly of the yeast vacuolar H+-ATPase". The Journal of Biological Chemistry. 274 (24): 17275–83. doi:10.1074/jbc.274.24.17275. PMID 10358087.
- Pearson H (9 January 2012). "Resurrecting extinct proteins shows how a machine evolves". Nature.com News Blog.
- Finnigan GC, Hanson-Smith V, Stevens TH, Thornton JW (January 2012). "Evolution of increased complexity in a molecular machine". Nature. 481 (7381): 360–4. Bibcode:2012Natur.481..360F. doi:10.1038/nature10724. PMC . PMID 22230956.
- Snapshot view of the V-ATPase molecular machine: animals vs. fungi, University of Oregon (Accessed 2012-01-11)
- Hilario E, Gogarten JP (1993). "Horizontal transfer of ATPase genes--the tree of life becomes a net of life" (PDF). Bio Systems. 31 (2-3): 111–9. doi:10.1016/0303-2647(93)90038-E. PMID 8155843.
- Kane PM, Smardon AM (August 2003). "Assembly and regulation of the yeast vacuolar H+-ATPase". Journal of Bioenergetics and Biomembranes. 35 (4): 313–21. doi:10.1023/A:1025724814656. PMID 14635777.
- Holliday LS, Lu M, Lee BS, Nelson RD, Solivan S, Zhang L, Gluck SL (October 2000). "The amino-terminal domain of the B subunit of vacuolar H+-ATPase contains a filamentous actin binding site". The Journal of Biological Chemistry. 275 (41): 32331–7. doi:10.1074/jbc.M004795200. PMID 10915794.
- Michigami T, Kageyama T, Satomura K, Shima M, Yamaoka K, Nakayama M, Ozono K (February 2002). "Novel mutations in the a3 subunit of vacuolar H(+)-adenosine triphosphatase in a Japanese patient with infantile malignant osteopetrosis". Bone. 30 (2): 436–9. doi:10.1016/S8756-3282(01)00684-6. PMID 11856654.
- 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 (July 2000). "Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis". Nature Genetics. 25 (3): 343–6. doi:10.1038/77131. PMID 10888887.
- Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, et al. (August 2001). "The mutational spectrum of human malignant autosomal recessive osteopetrosis". Human Molecular Genetics. 10 (17): 1767–73. doi:10.1093/hmg/10.17.176. PMID 11532986.
- Fasth A, Porras O (1999). "Human malignant osteopetrosis: pathophysiology, management and the role of bone marrow transplantation". Pediatric Transplantation. 3 Suppl 1 (Suppl 1): 102–7. doi:10.1034/j.1399-3046.1999.00063.x. PMID 10587979.
- Sly WS, Hewett-Emmett D, Whyte MP, Yu YS, Tashian RE (May 1983). "Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification". Proceedings of the National Academy of Sciences of the United States of America. 80 (9): 2752–6. Bibcode:1983PNAS...80.2752S. doi:10.1073/pnas.80.9.2752. PMC . PMID 6405388.
- Kornak U, Schulz A, Friedrich W, Uhlhaas S, Kremens B, Voit T, Hasan C, Bode U, Jentsch TJ, Kubisch C (August 2000). "Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis". Human Molecular Genetics. 9 (13): 2059–63. doi:10.1093/hmg/9.13.2059. PMID 10942435.
- 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 (October 2003). "Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis". Journal of Bone and Mineral Research. 18 (10): 1740–7. doi:10.1359/jbmr.2003.18.10.1740. PMID 14584882.
- Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F (September 2004). "TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA". Human Mutation. 24 (3): 225–35. doi:10.1002/humu.20076. PMID 15300850.
- Alper SL (2002). "Genetic diseases of acid-base transporters". Annual Review of Physiology. 64: 899–923. doi:10.1146/annurev.physiol.64.092801.141759. PMID 11826292.
- Karet FE, Finberg KE, Nelson RD, Nayir A, Mocan H, Sanjad SA, et al. (January 1999). "Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness". Nature Genetics. 21 (1): 84–90. doi:10.1038/5022. PMID 9916796.
- Stehberger PA, Schulz N, Finberg KE, Karet FE, Giebisch G, Lifton RP, Geibel JP, Wagner CA (December 2003). "Localization and regulation of the ATP6V0A4 (a4) vacuolar H+-ATPase subunit defective in an inherited form of distal renal tubular acidosis". Journal of the American Society of Nephrology. 14 (12): 3027–38. doi:10.1097/01.ASN.0000099375.74789.AB. PMID 14638902.
- Karet FE, Gainza FJ, Györy AZ, Unwin RJ, Wrong O, Tanner MJ, et al. (May 1998). "Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis". Proceedings of the National Academy of Sciences of the United States of America. 95 (11): 6337–42. Bibcode:1998PNAS...95.6337K. doi:10.1073/pnas.95.11.6337. PMC . PMID 9600966.
- Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, Rungroj N, et al. (November 2002). "Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss". Journal of Medical Genetics. 39 (11): 796–803. doi:10.1136/jmg.39.11.796. PMC . PMID 12414817.
- Ramachandran N, Munteanu I, Wang P, Ruggieri A, Rilstone JJ, Israelian N, et al. (March 2013). "VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy". Acta Neuropathologica. 125 (3): 439–57. doi:10.1007/s00401-012-1073-6. PMID 23315026.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
V-type ATPase 116kDa subunit family Provide feedback
This family consists of the 116kDa V-type ATPase (vacuolar (H+)-ATPases) subunits, as well as V-type ATP synthase subunit i. The V-type ATPases family are proton pumps that acidify intracellular compartments in eukaryotic cells for example yeast central vacuoles, clathrin-coated and synaptic vesicles. They have important roles in membrane trafficking processes . The 116kDa subunit (subunit a) in the V-type ATPase is part of the V0 functional domain responsible for proton transport. The a subunit is a transmembrane glycoprotein with multiple putative transmembrane helices it has a hydrophilic amino terminal and a hydrophobic carboxy terminal [1,2]. It has roles in proton transport and assembly of the V-type ATPase complex [1,2]. This subunit is encoded by two homologous gene in yeast VPH1 and STV1 .
Internal database links
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002490
Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.
There are several different types of transmembrane ATPases, which can differ in function (ATP hydrolysis and/or synthesis), structure (e.g., F-, V- and A-ATPases, which contain rotary motors) and in the type of ions they transport [PUBMED:15473999, PUBMED:15078220]. The different types include:
- F-ATPases (ATP synthases, F1F0-ATPases), which are found in mitochondria, chloroplasts and bacterial plasma membranes where they are the prime producers of ATP, using the proton gradient generated by oxidative phosphorylation (mitochondria) or photosynthesis (chloroplasts).
- V-ATPases (V1V0-ATPases), which are primarily found in eukaryotes and they function as proton pumps that acidify intracellular compartments and, in some cases, transport protons across the plasma membrane [PUBMED:20450191]. They are also found in bacteria [PUBMED:9741106].
- A-ATPases (A1A0-ATPases), which are found in Archaea and function like F-ATPases, though with respect to their structure and some inhibitor responses, A-ATPases are more closely related to the V-ATPases [PUBMED:18937357, PUBMED:1385979].
- P-ATPases (E1E2-ATPases), which are found in bacteria and in eukaryotic plasma membranes and organelles, and function to transport a variety of different ions across membranes.
- E-ATPases, which are cell-surface enzymes that hydrolyse a range of NTPs, including extracellular ATP.
V-ATPases (also known as V1V0-ATPase or vacuolar ATPase) (EC) are found in the eukaryotic endomembrane system, and in the plasma membrane of prokaryotes and certain specialised eukaryotic cells. V-ATPases hydrolyse ATP to drive a proton pump, and are involved in a variety of vital intra- and inter-cellular processes such as receptor mediated endocytosis, protein trafficking, active transport of metabolites, homeostasis and neurotransmitter release [PUBMED:15629643]. V-ATPases are composed of two linked complexes: the V1 complex (subunits A-H) contains the catalytic core that hydrolyses ATP, while the V0 complex (subunits a, c, c', c'', d) forms the membrane-spanning pore. V-ATPases may have an additional role in membrane fusion through binding to t-SNARE proteins [PUBMED:15907459].
This entry represents the 116kDa subunit (or subunit a) found in the V0 complex of V-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 [PUBMED:9891027].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||proton-transporting V-type ATPase, V0 domain (GO:0033179)|
|Molecular function||proton transmembrane transporter activity (GO:0015078)|
|Biological process||ATP hydrolysis coupled proton transport (GO:0015991)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_446 (release 4.0)|
|Author:||Bashton M , Bateman A|
|Number in seed:||257|
|Number in full:||5562|
|Average length of the domain:||447.90 aa|
|Average identity of full alignment:||23 %|
|Average coverage of the sequence by the domain:||80.71 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||19|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the V_ATPase_I domain has been found. There are 19 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
Loading structure mapping...