ATP5F1A explained

ATP synthase F1 subunit alpha, mitochondrial is an enzyme that in humans is encoded by the ATP5F1A gene.^{[1] [2]}

Function

This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F₁, and the membrane-spanning component, F_o, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the same protein have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16.^[2]

Structure

The ATP5F1A gene, located on the q arm of chromosome 18 in position 21, is made up of 13 exons and is 20,090 base pairs in length.^[2] The ATP5F1A protein weighs 59.7 kDa and is composed of 553 amino acids.^{[3] [4]} The protein is a subunit of the catalytic portion of the F₁F_o ATPase, also known as Complex V, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. As an alpha subunit, ATP5F1A is contained within the catalytic F₁ portion of the complex. The nomenclature of the enzyme has a long history. The F₁ fraction derives its name from the term "Fraction 1" and F_o (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for oligomycin, a type of naturally-derived antibiotic that is able to inhibit the F_o unit of ATP synthase.^{[5] [6]} The F₁ particle is large and can be seen in the transmission electron microscope by negative staining.^[7] These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but, through a long series of experiments, Efraim Racker and his colleagues (who first isolated the F₁ particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.

Function

Mitochondrial membrane ATP synthase (F₁F_o ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F₁ - containing the extramembraneous catalytic core, and F_o - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F₁ is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Subunits alpha and beta form the catalytic core in F₁. Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits. Subunit alpha does not bear the catalytic high-affinity ATP-binding sites.^[8]

Clinical significance

Mutations affecting the ATP5F1A gene cause combined oxidative phosphorylation deficiency 22 (COXPD22), a mitochondrial disorder characterized by intrauterine growth retardation, microcephaly, hypotonia, pulmonary hypertension, failure to thrive, encephalopathy, and heart failure. Mutations on the ATP5F1A gene also cause mitochondrial complex V deficiency, nuclear 4 (MC5DN4), a mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid.^[9]

Resveratrol inhibition of the F1 catalytic core increases adenosine monophosphate (AMP) levels, thereby activating the AMP-activated protein kinase enzyme.^[10]

Further reading

• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Kovalyov LI, Shishkin SS, Efimochkin AS, Kovalyova MA, Ershova ES, Egorov TA, Musalyamov AK . The major protein expression profile and two-dimensional protein database of human heart . Electrophoresis . 16 . 7 . 1160–9 . July 1995 . 7498159 . 10.1002/elps.11501601192 . 32209361 .
• Abrahams JP, Leslie AG, Lutter R, Walker JE . Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria . Nature . 370 . 6491 . 621–8 . August 1994 . 8065448 . 10.1038/370621a0 . 1994Natur.370..621A . 4275221 .
• Akiyama S, Endo H, Inohara N, Ohta S, Kagawa Y . Gene structure and cell type-specific expression of the human ATP synthase alpha subunit . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1219 . 1 . 129–40 . September 1994 . 8086450 . 10.1016/0167-4781(94)90255-0 .
• Jabs EW, Thomas PJ, Bernstein M, Coss C, Ferreira GC, Pedersen PL . Chromosomal localization of genes required for the terminal steps of oxidative metabolism: alpha and gamma subunits of ATP synthase and the phosphate carrier . Human Genetics . 93 . 5 . 600–2 . May 1994 . 8168843 . 10.1007/bf00202832 . 39597611 .
• Godbout R, Bisgrove DA, Honoré LH, Day RS . Amplification of the gene encoding the alpha-subunit of the mitochondrial ATP synthase complex in a human retinoblastoma cell line . Gene . 123 . 2 . 195–201 . January 1993 . 8428659 . 10.1016/0378-1119(93)90124-L .
• Godbout R, Pandita A, Beatty B, Bie W, Squire JA . Comparative genomic hybridization analysis of Y79 and FISH mapping indicate the amplified human mitochondrial ATP synthase alpha-subunit gene (ATP5A) maps to chromosome 18q12-->q21 . Cytogenetics and Cell Genetics . 77 . 3–4 . 253–6 . 1997 . 9284928 . 10.1159/000134588 .
• Elston T, Wang H, Oster G . Energy transduction in ATP synthase . Nature . 391 . 6666 . 510–3 . January 1998 . 9461222 . 10.1038/35185 . 1998Natur.391..510E . 4406161 .
• Wang H, Oster G . Energy transduction in the F1 motor of ATP synthase . Nature . 396 . 6708 . 279–82 . November 1998 . 9834036 . 10.1038/24409 . 1998Natur.396..279W . 4424498 .
• Moser TL, Stack MS, Asplin I, Enghild JJ, Højrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV . Angiostatin binds ATP synthase on the surface of human endothelial cells . Proceedings of the National Academy of Sciences of the United States of America . 96 . 6 . 2811–6 . March 1999 . 10077593 . 15851 . 10.1073/pnas.96.6.2811 . 1999PNAS...96.2811M . free .
• Moser TL, Kenan DJ, Ashley TA, Roy JA, Goodman MD, Misra UK, Cheek DJ, Pizzo SV . Endothelial cell surface F1-F0 ATP synthase is active in ATP synthesis and is inhibited by angiostatin . Proceedings of the National Academy of Sciences of the United States of America . 98 . 12 . 6656–61 . June 2001 . 11381144 . 34409 . 10.1073/pnas.131067798 . 2001PNAS...98.6656M . free .
• Wang ZG, White PS, Ackerman SH . Atp11p and Atp12p are assembly factors for the F(1)-ATPase in human mitochondria . The Journal of Biological Chemistry . 276 . 33 . 30773–8 . August 2001 . 11410595 . 10.1074/jbc.M104133200 . free .
• Chang SY, Park SG, Kim S, Kang CY . Interaction of the C-terminal domain of p43 and the alpha subunit of ATP synthase. Its functional implication in endothelial cell proliferation . The Journal of Biological Chemistry . 277 . 10 . 8388–94 . March 2002 . 11741979 . 10.1074/jbc.M108792200 . free .
• Sergeant N, Wattez A, Galván-valencia M, Ghestem A, David JP, Lemoine J, Sautiére PE, Dachary J, Mazat JP, Michalski JC, Velours J, Mena-López R, Delacourte A . Association of ATP synthase alpha-chain with neurofibrillary degeneration in Alzheimer's disease . Neuroscience . 117 . 2 . 293–303 . 2003 . 12614671 . 10.1016/S0306-4522(02)00747-9 . 43991411 .
• Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• Cross RL . Molecular motors: turning the ATP motor . Nature . 427 . 6973 . 407–8 . January 2004 . 14749816 . 10.1038/427407b . 2004Natur.427..407C . 52819856 . free .
• Jin J, Smith FD, Stark C, Wells CD, Fawcett JP, Kulkarni S, Metalnikov P, O'Donnell P, Taylor P, Taylor L, Zougman A, Woodgett JR, Langeberg LK, Scott JD, Pawson T . Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization . Current Biology . 14 . 16 . 1436–50 . August 2004 . 15324660 . 10.1016/j.cub.2004.07.051 . free .

Notes and References

1. Kataoka H, Biswas C . Nucleotide sequence of a cDNA for the alpha subunit of human mitochondrial ATP synthase . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1089 . 3 . 393–5 . July 1991 . 1830491 . 10.1016/0167-4781(91)90183-m .
2. Web site: Entrez Gene: ATP5F1A ATP synthase F1 subunit alpha.
3. Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . October 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
4. Web site: ATP synthase subunit alpha, mitochondrial . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 2018-07-18 . https://web.archive.org/web/20180720130552/https://amino.heartproteome.org/web/protein/P25705 . 2018-07-20 . dead .
5. Kagawa Y, Racker E . Partial resolution of the enzymes catalyzing oxidative phosphorylation. 8. Properties of a factor conferring oligomycin sensitivity on mitochondrial adenosine triphosphatase . The Journal of Biological Chemistry . 241 . 10 . 2461–6 . May 1966 . 10.1016/S0021-9258(18)96640-8 . 4223640 . free .
6. Mccarty RE . A PLANT BIOCHEMIST'S VIEW OF H+-ATPases AND ATP SYNTHASES . The Journal of Experimental Biology . 172 . Pt 1 . 431–441 . November 1992 . 10.1242/jeb.172.1.431 . 9874753 .
7. Fernandez Moran H, Oda T, Blair PV, Green DE . A Macromolecular Repeating Unit Of Mitochondrial Structure and Function. Correlated Electron Microscopic and Biochemical Studies of Isolated Mitochondria and Submitochondrial Particles of Beef Heart Muscle . The Journal of Cell Biology . 22 . 1 . 63–100 . July 1964 . 14195622 . 2106494 . 10.1083/jcb.22.1.63 .
8. Web site: ATP synthase subunit alpha, mitochondrial . UniProt . The UniProt Consortium .
9. Web site: ATP5F1A . NCBI Genetics Home Resource .
10. Joshi T, Singh AK, Haratipour P, Farzaei MH . Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications . . 234 . 10 . 17212–17231 . 2019 . 10.1002/jcp.28528 . 30916407. 85533334 .