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37  structures 314  species 4  interactions 375  sequences 6  architectures

Family: ATP-synt_Eps (PF04627)

Summary: Mitochondrial ATP synthase epsilon chain

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ATP5E Edit Wikipedia article

ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit
Protein ATP5E PDB 1e79.png
PDB rendering based on 1e79.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols ATP5E ; ATPE; MC5DN3
External IDs OMIM606153 HomoloGene128187 GeneCards: ATP5E Gene
EC number 3.6.3.14
RNA expression pattern
PBB GE ATP5E 217801 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 514 n/a
Ensembl ENSG00000124172 n/a
UniProt P56381 n/a
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 [1] n/a
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
Symbol ATP-synt_Eps
Pfam PF04627
InterPro IPR006721
SCOP 1e79
SUPERFAMILY 1e79

ATP synthase subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5E gene.[1][2]

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 a single representative of the other 3. 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.[2]

Structure

The ATP5E 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.[2] The ATP5A1 protein weighs 5.7 kDa and is composed of 51 amino acids.[3][4] The protein is a subunit of the F1Fo ATPase, also known as Complex V, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. As an alpha subunit, ATP5A1 is contained within the catalytic F1 portion of the complex and acts as a regulatory subunit that inhibits the binding of ADP, preventing wasteful ATP production.[2] 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.[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 (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).[8]

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.[9]

Clinical significance

Mutations in the ATP5E 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.[10]

Reduced expression of ATP5E is significantly associated with the diagnosis of Papillary Thyroid Cancer and may serve as an early tumor marker of the disease.[11] Papillary Thyroid Cancer is the most common type of thyroid cancer,[12] representing 75 percent to 85 percent of all thyroid cancer cases.[13] 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.[14]

References

  1. ^ Tu Q, Yu L, Zhang P, Zhang M, Zhang H, Jiang J, Chen C, Zhao S (Jun 2000). "Cloning, characterization and mapping of the human ATP5E gene, identification of pseudogene ATP5EP1, and definition of the ATP5E motif". Biochem J 347 (1): 17–21. doi:10.1042/0264-6021:3470017. PMC 1220925. PMID 10727396. 
  2. ^ a b c d "Entrez Gene: ATP5E ATP synthase, H+ transporting, mitochondrial F1 complex, epsilon subunit". 
  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 (Oct 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. 
  4. ^ "ATP synthase subunit epsilon, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  5. ^ Kagawa Y, Racker E. (1966). "Partial resolution of the enzymes catalyzing oxidative phosphorylation. 8. Properties of a factor conferring oligomycin sensitivity on mitochondrial adenosine triphosphatase.". Journal of Biological Chemistry 241: 2461–2466. PMID 4223640. 
  6. ^ Mccarty RE (November 1992). "A plant biochemist's view of H+
    -ATPases and ATP synthases"
    . J. Exp. Biol. 172 (Pt 1): 431–441. PMID 9874753.
     
  7. ^ Fernández-Morán 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". J. Cell Biol. 22 (1): 63–100. doi:10.1083/jcb.22.1.63. PMC 2106494. PMID 14195622. 
  8. ^ "ATP synthase subunit epsilon, mitochondrial". UniProt. The UniProt Consortium. 
  9. ^ 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 Lett. 579 (23): 5114–8. doi:10.1016/j.febslet.2005.08.030. PMID 16154570. 
  10. ^ "ATP5E". Genetics Home Resource. NCBI. 
  11. ^ Hurtado-López, LM; Fernández-Ramírez, F; Martínez-Peñafiel, E; Carrillo Ruiz, JD; Herrera González, NE (16 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 : international medical journal of experimental and clinical research 21: 1745–51. doi:10.12659/MSM.893597. PMID 26079849. 
  12. ^ Hu MI, Vassilopoulou-Sellin R, Lustig R, Lamont JP "Thyroid and Parathyroid Cancers" in Pazdur R, Wagman LD, Camphausen KA, Hoskins WJ (Eds) Cancer Management: A Multidisciplinary Approach. 11 ed. 2008.
  13. ^ Chapter 20 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K; Fausto, Nelson. Robbins Basic Pathology. Philadelphia: Saunders. ISBN 1-4160-2973-7.  8th edition.
  14. ^ Dinets A, Hulchiy M, Sofiadis A, Ghaderi M, Höög A, Larsson C, Zedenius J (2012). "Clinical, Genetic and Immunohistochemical Characterization of 70 Ukrainian Adult Cases with Post-Chornobyl Papillary Thyroid Carcinoma". Eur J Endocrinol 166: 1049–60. doi:10.1530/EJE-12-0144. PMC 3361791. PMID 22457234. 

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

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

Mitochondrial ATP synthase epsilon chain Provide feedback

This family constitutes the mitochondrial ATP synthase epsilon subunit. This is not to be confused with the bacterial epsilon subunit, which is homologous to the mitochondrial delta subunit (PF00401 and PF02823) The epsilon subunit is located in the extrinsic membrane section F1, which is the catalytic site of ATP synthesis. The epsilon subunit was not well ordered in the crystal structure of bovine F1 [1] but it is known to be located in the stalk region of F1 [2]. E subunit is thought to be involved in the regulation of ATP synthase, since a null mutation increased oligomycin sensitivity and decreased inhibition by inhibitor protein IF1 [2].

Literature references

  1. Abrahams JP, Leslie AG, Lutter R, Walker JE; , Nature 1994;370:621-628.: Structure at 2.8 A resolution of F1-ATPase from bovine heart mitochondria. PUBMED:8065448 EPMC:8065448

  2. Tu Q, Yu L, Zhang P, Zhang M, Zhang H, Jiang J, Chen C, Zhao S; , Biochem J 2000;347:17-21.: Cloning, characterization and mapping of the human ATP5E gene, identification of pseudogene ATP5EP1, and definition of the ATP5E motif. PUBMED:10727396 EPMC:10727396


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006721

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 (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 eukaryotic 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.

F-ATPases (also known as F1F0-ATPase, or H(+)-transporting two-sector ATPase) (EC) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), nine in mitochondria (A-G, F6, F8). Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the alpha(3)beta(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis [PUBMED:11309608]. These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This family constitutes the mitochondrial ATP synthase epsilon subunit, which is distinct from the bacterial epsilon subunit (the latter being homologous to the mitochondrial delta subunit, INTERPRO). The mitochondrial 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 extended epsilon subunit is thought to become extended in the presence of ADP, thereby acting as a safety lock to prevent wasteful ATP hydrolysis [PUBMED:16154570].

Gene Ontology

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Domain organisation

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RP75
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  Seed
(113)
Full
(375)
Representative proteomes UniProt
(915)
NCBI
(810)
Meta
(1)
RP15
(104)
RP35
(204)
RP55
(300)
RP75
(366)
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  Seed
(113)
Full
(375)
Representative proteomes UniProt
(915)
NCBI
(810)
Meta
(1)
RP15
(104)
RP35
(204)
RP55
(300)
RP75
(366)
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Curation and family details

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Seed source: DOMO:DM04624;
Previous IDs: ATP-synt_E;
Type: Family
Author: Kerrison ND
Number in seed: 113
Number in full: 375
Average length of the domain: 47.80 aa
Average identity of full alignment: 41 %
Average coverage of the sequence by the domain: 50.99 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 11927849 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 24.2 23.2
Noise cut-off 18.9 18.8
Model length: 49
Family (HMM) version: 10
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Interactions

There are 4 interactions for this family. More...

ATP-synt_ab_C ATP-synt_DE_N ATP-synt ATP-synt_C

Structures

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 ATP-synt_Eps domain has been found. There are 37 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 seqence.

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