ATP synthase, H+ transporting, mitochondrial F1 complex, alpha 1

ATP5A1
Identifiers
Aliases	ATP5A1, 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
External IDs	MGI: 88115 HomoloGene: 2985 GeneCards: ATP5A1
Gene ontology Molecular function • nucleotide binding • proton-transporting ATP synthase activity, rotational mechanism • transmembrane transporter activity • proton-transporting ATPase activity, rotational mechanism • ATPase activity • protein binding • hydrolase activity, acting on acid anhydrides, catalyzing transmembrane movement of substances • MHC class I protein binding • poly(A) RNA binding • ATP binding • adenyl ribonucleotide binding Cellular component • mitochondrial proton-transporting ATP synthase complex • membrane • myelin sheath • plasma membrane • mitochondrial matrix • mitochondrion • proton-transporting two-sector ATPase complex, catalytic domain • mitochondrial inner membrane • proton-transporting ATP synthase complex, catalytic core F(1) • COP9 signalosome • extracellular exosome • extracellular matrix Biological process • embryo development • lipid metabolic process • mitochondrial ATP synthesis coupled proton transport • ion transport • proton transport • negative regulation of endothelial cell proliferation • ATP metabolic process • transport • ATP synthesis coupled proton transport • ATP hydrolysis coupled proton transport • ATP biosynthetic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
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_001001935.1 NP_001001937.1 NP_001244263.1 NP_001244264.1 NP_004037.1	NP_031531.1
Location (UCSC)	Chr 18: 46.08 – 46.1 Mb	Chr 18: 77.77 – 77.78 Mb
PubMed search	[1]	[2]
Wikidata

ATP synthase subunit alpha, mitochondrial is an enzyme that in humans is encoded by the ATP5A1 gene.^[3][4]

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.^[4]

Structure

The ATP5A1 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.^[4] The ATP5A1 protein weighs 59.7 kDa and is composed of 553 amino acids.^[5][6] 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, ATP5A1 is contained within the catalytic F₁ portion of the complex.^[4] 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.^[7][8] The F₁ particle is large and can be seen in the transmission electron microscope by negative staining.^[9] 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.^[10]

Clinical significance

Mutations affecting the ATP5A1 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 ATP5A1 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.^[11]

Model organisms

Model organisms have been used in the study of ATP5A1 function. A conditional knockout mouse line, called Atp5a1^{tm1a(EUCOMM)Wtsi[18][19]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[20][21][22]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[16][23] Twenty two tests were carried out on mutant mice and five significant abnormalities were observed.^[16] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and decreased body weight, lean body mass and hypoproteinemia was observed in female animals.^[16]

References

Further reading

PDB gallery
1bmf: BOVINE MITOCHONDRIAL F1-ATPASE  1cow: BOVINE MITOCHONDRIAL F1-ATPASE COMPLEXED WITH AUROVERTIN B  1e1q: BOVINE MITOCHONDRIAL F1-ATPASE AT 100K  1e1r: BOVINE MITOCHONDRIAL F1-ATPASE INHIBITED BY MG2+ADP AND ALUMINIUM FLUORIDE  1e79: BOVINE F1-ATPASE INHIBITED BY DCCD (DICYCLOHEXYLCARBODIIMIDE)  1efr: BOVINE MITOCHONDRIAL F1-ATPASE COMPLEXED WITH THE PEPTIDE ANTIBIOTIC EFRAPEPTIN  1h8e: (ADP.ALF4)2(ADP.SO4) BOVINE F1-ATPASE (ALL THREE CATALYTIC SITES OCCUPIED)  1h8h: BOVINE MITOCHONDRIAL F1-ATPASE CRYSTALLISED IN THE PRESENCE OF 5MM AMPPNP  1mab: RAT LIVER F1-ATPASE  1nbm: THE STRUCTURE OF BOVINE F1-ATPASE COVALENTLY INHIBITED WITH 4-CHLORO-7-NITROBENZOFURAZAN  1ohh: BOVINE MITOCHONDRIAL F1-ATPASE COMPLEXED WITH THE INHIBITOR PROTEIN IF1  1w0j: BERYLLIUM FLUORIDE INHIBITED BOVINE F1-ATPASE  1w0k: BERYLLIUM FLUORIDE INHIBITED BOVINE F1-ATPASE  2ck3: AZIDE INHIBITED BOVINE F1-ATPASE  2f43: Rat liver F1-ATPase  2jdi: GROUND STATE STRUCTURE OF F1-ATPASE FROM BOVINE HEART MITOCHONDRIA (BOVINE F1-ATPASE CRYSTALLISED IN THE ABSENCE OF AZIDE)

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