ATP5E

ATP synthase F1 subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5F1E gene. The protein encoded by ATP5F1E is a subunit of ATP synthase, also known as Complex V. Variations of this gene have been associated with a condition called mitochondrial complex V deficiency, nuclear 3 (MC5DN3) and papillary thyroid cancer.

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. The ATP5F1E protein weighs 5.7 kDa and is composed of 51 amino acids. Two pseudogenes of this gene are located on chromosomes 4 and 13.

Naming
This gene is named for the subunit it encodes of the version of ATP synthase found in mitochondria. Mitochondrial ATP synthase catalyzes ATP synthesis through the difference in protein concentrations across a cellular membrane. ATP synthase is composed of two linked multi-subunit complexes, each composed of multiple proteins: the water-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 kinds of subunits (alpha, beta, gamma, delta, and epsilon), each catalytic core containing 3 alpha, 3 beta, one gamma, one delta, and one epsilon. This gene encodes the epsilon subunit of the catalytic core.

Function
Mitochondrial membrane ATP synthase (F1Fo ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient (difference in proton concentration) across the membrane generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains or parts: F1, which contains the catalytic core outside of the membrane; and Fo, which contains the proton channel reaching across the membrane; both linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the active site of F1 is coupled, through a mechanism involving the rotation of the central stalk, to the motion of protons across the membrane. ATP5F1E is part of the F1 domain, and more specifically part of the rotating central stalk. Rotation of the central stalk against the surrounding alpha3beta3 subunits, leads to the hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity).

Being located in the stalk region of the F1 complex, the epsilon unit acts as an inhibitor of the active site of the ATPase. The epsilon subunit can assume two conformations, or shapes: contracted and extended. The latter inhibits ATP hydrolysis, while the former does not. The conformation of the epsilon subunit is determined by the direction of rotation of the gamma subunit of the ATPase, 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 the wasteful degradation of ATP to ADP through hydrolysis.

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. 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.

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. Papillary Thyroid Cancer is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. 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.

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.