ATP5E

Last updated
ATP5F1E
Protein ATP5E PDB 1e79.png
Identifiers
Aliases ATP5F1E , ATPE, MC5DN3, ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit, ATP synthase F1 subunit epsilon, ATP5E
External IDs OMIM: 606153 HomoloGene: 128187 GeneCards: ATP5F1E
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_006886

n/a

RefSeq (protein)

NP_008817

n/a

Location (UCSC) Chr 20: 59.03 – 59.03 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human
Mitochondrial ATP synthase epsilon chain
PDB 2jdi EBI.jpg
ground state structure of f1-atpase from bovine heart mitochondria (bovine f1-atpase crystallised in the absence of azide)
Identifiers
SymbolATP-synt_Eps
Pfam PF04627
InterPro IPR006721
SCOP2 1e79 / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

ATP synthase F1 subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5F1E gene. [3] [4] The protein encoded by ATP5F1E is a subunit of ATP synthase, also known as Complex V. Variations of this gene have been associated with mitochondrial complex V deficiency, nuclear 3 (MC5DN3) and Papillary Thyroid Cancer. [5] [6]

Contents

Function

This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing 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 one each of gamma, delta and epsilon. The proton channel consists of three main subunits (a, b, c). This gene encodes the epsilon subunit of the catalytic core. Two pseudogenes of this gene are located on chromosomes 4 and 13. [4]

Structure

The ATP5F1E gene, located on the q arm of chromosome 20 in position 13.32, is made up of 3 exons and is 3,690 base pairs in length. [4] The ATP5F1E protein weighs 5.7 kDa and is composed of 51 amino acids. [7] [8] The protein is a subunit of the F1Fo ATPase, also known as Complex V, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. 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

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. Part of the complex F1 domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity). [12]

The epsilon subunit is located in the stalk region of the F1 complex, and acts as an inhibitor of the ATPase catalytic core. The epsilon subunit can assume two conformations, contracted and extended, where the latter inhibits ATP hydrolysis. The conformation of the epsilon subunit is determined by the direction of rotation of the gamma subunit, and possibly by the presence of ADP. The epsilon subunit is thought to become extended in the presence of ADP, thereby acting as a safety lock to prevent wasteful ATP hydrolysis. [13]

Clinical significance

Mutations in the ATP5F1E gene cause mitochondrial complex V deficiency, nuclear 3 (MC5DN3), 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. [5] Pathogenic variations have included a homozygous Tyr12Cys mutation in the ATP5E gene, which has been linked with neonatal onset complex V deficiency with lactic acidosis, 3-methylglutaconic aciduria, mild mental retardation and developed peripheral neuropathy. [14]

Reduced expression of ATP5F1E is significantly associated with the diagnosis of Papillary Thyroid Cancer and may serve as an early tumor marker of the disease. [6] Papillary Thyroid Cancer is the most common type of thyroid cancer, [15] representing 75 percent to 85 percent of all thyroid cancer cases. [16] It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck. [17]

Interactions

ATP5F1E has been shown to have 34 binary protein-protein interactions including 28 co-complex interactions. ATP5F1E appears to interact with ATP5F1D, AGTRAP, CYP17A1, UBE2N. [18]

Related Research Articles

A proton pump is an integral membrane protein pump that builds up a proton gradient across a biological membrane. Proton pumps catalyze the following reaction:

<span class="mw-page-title-main">ATP synthase</span> Enzyme

ATP synthase is an enzyme that catalyzes the formation of the energy storage molecule adenosine triphosphate (ATP) using adenosine diphosphate (ADP) and inorganic phosphate (Pi). ATP synthase is a molecular machine. The overall reaction catalyzed by ATP synthase is:

<span class="mw-page-title-main">MT-ATP8</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP8 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 8' that encodes a subunit of mitochondrial ATP synthase, ATP synthase Fo subunit 8. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Subunit 8 differs in sequence between Metazoa, plants and Fungi.

<span class="mw-page-title-main">ATP5B</span> Protein-coding gene in humans

ATP synthase F1 subunit beta, mitochondrial is an enzyme that in humans is encoded by the ATP5F1B gene.

<span class="mw-page-title-main">ATP5F1A</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">ATP5PF</span> Protein-coding gene in the species Homo sapiens

ATP synthase-coupling factor 6, mitochondrial is an enzyme subunit that in humans is encoded by the ATP5PF gene.

<span class="mw-page-title-main">ATP5G1</span> Protein-coding gene in the species Homo sapiens

The ATP5MC1 gene is one of three human paralogs that encode membrane subunit c of the mitochondrial ATP synthase.

<span class="mw-page-title-main">ATP5J2</span> Protein-coding gene in the species Homo sapiens

The ATP5MF gene encodes the ATP synthase subunit f, mitochondrial enzyme in humans.

<span class="mw-page-title-main">ATP synthase alpha/beta subunits</span>

The alpha and beta subunits are found in the F1, V1, and A1 complexes of F-, V- and A-ATPases, respectively, as well as flagellar (T3SS) ATPase and the termination factor Rho. The subunits make up a ring that contains the ATP-hydrolyzing catalytic core. The F-ATPases, V-ATPases and A-ATPases are composed of two linked complexes: the F1, V1 or A1 complex containsthat synthesizes/hydrolyses ATP, and the Fo, Vo or Ao complex that forms the membrane-spanning pore. The F-, V- and A-ATPases all contain rotary motors, one that drives proton translocation across the membrane and one that drives ATP synthesis/hydrolysis.

<span class="mw-page-title-main">ATP synthase delta/OSCP subunit</span> Subunit of bacterial and chloroplast F-ATPase/synthase

ATP synthase delta subunit is a subunit of bacterial and chloroplast F-ATPase/synthase. It is known as OSCP in mitochondrial ATPase.

<span class="mw-page-title-main">ATP5L</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit g, mitochondrial is an enzyme that in humans is encoded by the ATP5MG gene.

<span class="mw-page-title-main">ATP synthase gamma subunit</span>

Gamma subunit of ATP synthase F1 complex forms the central shaft that connects the Fo rotary motor to the F1 catalytic core. F-ATP synthases are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits, while the Fo ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), nine in mitochondria.

<span class="mw-page-title-main">ATP5C1</span> Protein-coding gene in the species Homo sapiens

The human ATP5F1C gene encodes the gamma subunit of an enzyme called mitochondrial ATP synthase.

<span class="mw-page-title-main">ATP5F1</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit b, mitochondrial is an enzyme that in humans is encoded by the ATP5PB gene.

<span class="mw-page-title-main">ATP5S</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit s, mitochondrial is an enzyme that in humans is encoded by the ATP5S gene.

<span class="mw-page-title-main">ATP5G2</span> Protein-coding gene in humans

The ATP5MC2 gene is one of three human paralogs that encode membrane subunit c of the mitochondrial ATP synthase.

<span class="mw-page-title-main">ATP5I</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit e, mitochondrial is an enzyme that in humans is encoded by the ATP5ME gene.

<span class="mw-page-title-main">ATP5H</span> Protein-coding gene in the species Homo sapiens

The human gene ATP5PD encodes subunit d of the peripheral stalk part of the enzyme mitochondrial ATP synthase.

<span class="mw-page-title-main">ATP5D</span> Protein-coding gene in the species Homo sapiens

ATP synthase subunit delta, mitochondrial, also known as ATP synthase F1 subunit delta or F-ATPase delta subunit is an enzyme that in humans is encoded by the ATP5F1D gene. This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation.

<span class="mw-page-title-main">ATP5G3</span> Protein-coding gene in the species Homo sapiens

The ATP5MC3 gene is one of three human paralogs that encode membrane subunit c of the mitochondrial ATP synthase.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000124172 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. Tu Q, Yu L, Zhang P, Zhang M, Zhang H, Jiang J, Chen C, Zhao S (April 2000). "Cloning, characterization and mapping of the human ATP5E gene, identification of pseudogene ATP5EP1, and definition of the ATP5E motif". The Biochemical Journal. 347 (1): 17–21. doi:10.1042/0264-6021:3470017. PMC   1220925 . PMID   10727396.
  4. 1 2 3 "Entrez Gene: ATP5F1E ATP synthase F1 subunit epsilon".
  5. 1 2 "ATP5F1E". Genetics Home Resource. NCBI.
  6. 1 2 Hurtado-López LM, Fernández-Ramírez F, Martínez-Peñafiel E, Carrillo Ruiz JD, Herrera González NE (June 2015). "Molecular Analysis by Gene Expression of Mitochondrial ATPase Subunits in Papillary Thyroid Cancer: Is ATP5E Transcript a Possible Early Tumor Marker?". Medical Science Monitor. 21: 1745–51. doi:10.12659/MSM.893597. PMC   4482184 . PMID   26079849.
  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 epsilon, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).[ permanent dead link ]
  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 epsilon, mitochondrial". UniProt. The UniProt Consortium.
  13. Feniouk BA, Junge W (September 2005). "Regulation of the F0F1-ATP synthase: the conformation of subunit epsilon might be determined by directionality of subunit gamma rotation". FEBS Letters. 579 (23): 5114–8. doi: 10.1016/j.febslet.2005.08.030 . PMID   16154570. S2CID   84231010.
  14. Mayr JA, Havlícková V, Zimmermann F, Magler I, Kaplanová V, Jesina P, Pecinová A, Nusková H, Koch J, Sperl W, Houstek J (September 2010). "Mitochondrial ATP synthase deficiency due to a mutation in the ATP5E gene for the F1 epsilon subunit". Human Molecular Genetics. 19 (17): 3430–9. doi: 10.1093/hmg/ddq254 . PMID   20566710.
  15. Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP "Thyroid and Parathyroid Cancers" Archived 2010-02-28 at the Wayback Machine in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach Archived 2013-10-04 at the Wayback Machine . 11 ed. 2008.
  16. Chapter 20 in: Mitchell, Richard Sheppard, Kumar, Vinay, Abbas, Abul K, Fausto, Nelson (2007). Robbins Basic Pathology. Philadelphia: Saunders. ISBN   978-1-4160-2973-1. 8th edition.
  17. Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, Höög A, Larsson C, Zedenius J (June 2012). "Clinical, genetic, and immunohistochemical characterization of 70 Ukrainian adult cases with post-Chornobyl papillary thyroid carcinoma". European Journal of Endocrinology. 166 (6): 1049–60. doi:10.1530/EJE-12-0144. PMC   3361791 . PMID   22457234.
  18. "34 binary interactions found for search term ATP5F1E". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-11-21.

Further reading

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

This article incorporates text from the public domain Pfam and InterPro: IPR006721