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ATP5F1A

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ATP5F1A
Identifiers
AliasesATP5F1A, ATP5A, ATP5AL2, ATPM, HEL-S-123m, MC5DN4, MOM2, OMR, ORM, hATP1, COXPD22, ATP synthase, H+ transporting, mitochondrial F1 complex, alpha 1, ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1, cardiac muscle, ATP5A1, ATP synthase F1 subunit alpha
External IDsOMIM: 164360; MGI: 88115; HomoloGene: 2985; GeneCards: ATP5F1A; OMA:ATP5F1A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

498

11946

Ensembl

ENSG00000152234

ENSMUSG00000025428

UniProt

P25705

Q03265

RefSeq (mRNA)

NM_001001935
NM_001001937
NM_001257334
NM_001257335
NM_004046

NM_007505

RefSeq (protein)

NP_001001935
NP_001001937
NP_001244263
NP_001244264
NP_004037

NP_031531

Location (UCSC)Chr 18: 46.08 – 46.1 MbChr 18: 77.86 – 77.87 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATP synthase F1 subunit alpha, mitochondrial is an enzyme that in humans is encoded by the ATP5F1A gene.[5][6]

Function

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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, Fo, 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.[6]

Structure

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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.[6] The ATP5F1A protein weighs 59.7 kDa and is composed of 553 amino acids.[7][8] The protein is a subunit of the catalytic portion of the F1Fo 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.[6] The nomenclature of the enzyme has a long history. The F1 fraction derives its name from the term "Fraction 1" and Fo (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 Fo unit of ATP synthase.[9][10] The F1 particle is large and can be seen in the transmission electron microscope by negative staining.[11] 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

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Mitochondrial membrane ATP synthase (F1Fo 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 Fo - 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.[12]

Clinical significance

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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.[13]

Resveratrol inhibition of the F1 catalytic core increases adenosine monophosphate (AMP) levels, thereby activating the AMP-activated protein kinase enzyme.[14]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000152234 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025428 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Kataoka H, Biswas C (July 1991). "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. doi:10.1016/0167-4781(91)90183-m. PMID 1830491.
  6. ^ a b c d "Entrez Gene: ATP5F1A ATP synthase F1 subunit alpha".
  7. ^ 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 (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338.
  8. ^ "ATP synthase subunit alpha, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2018-07-20. Retrieved 2018-07-18.
  9. ^ Kagawa Y, Racker E (May 1966). "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. doi:10.1016/S0021-9258(18)96640-8. PMID 4223640.
  10. ^ Mccarty RE (November 1992). "A PLANT BIOCHEMIST'S VIEW OF H+-ATPases AND ATP SYNTHASES". The Journal of Experimental Biology. 172 (Pt 1): 431–441. doi:10.1242/jeb.172.1.431. PMID 9874753.
  11. ^ Fernandez Moran H, Oda T, Blair PV, Green DE (July 1964). "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. doi:10.1083/jcb.22.1.63. PMC 2106494. PMID 14195622.
  12. ^ "ATP synthase subunit alpha, mitochondrial". UniProt. The UniProt Consortium.
  13. ^ "ATP5F1A". NCBI Genetics Home Resource.
  14. ^ Joshi T, Singh AK, Haratipour P, Farzaei MH (2019). "Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications". Journal of Cellular Physiology. 234 (10): 17212–17231. doi:10.1002/jcp.28528. PMID 30916407. S2CID 85533334.

Further reading

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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