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ATP/ADP translocase is a transporter protein that enables ATP and ADP to transverse the inner mitochondrial membrane. ATP is transported from the mitochondrial matrix, where it is produced by oxidative phosphorylation, to the cytoplasm, whereas ADP is transported from the cytoplasm to the mitochondrial matrix. More than 10% of the protein in the inner mitochondrial membrane consists of ATP/ADP translocase.

Structure
The ATP/ADP translocase is a homodimer with each subunit consisting of 297 residues and weighing approximately 30 kDa. Each subunit consists of six transmembrane α-helices that form a barrel that results in a deep cone-shaped depression accessible from the outside where the substrate binds. The binding pocket consists of mostly basic residues that allow for strong binding to ATP or ADP, many of which are conserved throughout isoforms, and has a maximal diameter of 20 A and a depth of 30 A. Indeed, arginine 96, 204, 252, 253, and 294, as well as lysine 38, have been shown to be essential for transporter activity.

Translocase Mechanism
Under normal conditions, ATP and ADP cannot cross the inner mitochondrial membrane due to their high negative charges, but ATP/ADP translocase, an antiporter, couples the transport of the two molecules. The depression in ATP/ADP translocase alternatively faces the matrix and the cytoplasmic sides of the membrane. ADP binding from the cytoplasm induces eversion of the transporter and results in the release of ADP into the matrix. Binding of ATP from the matrix induces eversion and results in the release of ATP into the cytoplasm and concomitantly brings the translocase back to its original conformation. ATP and ADP are the only natural nucleotides recognized by the translocase.

The net process is denoted by:
 * ATP3-cytoplasm + ATP4-matrix → ATP3-matrix + ATP4-cytoplasm

ATP-ADP exchange is energetically expensive: about 25% of the energy yielded from electron transfer by aerobic respiration, or one hydrogen ion, is consumed to regenerate the membrane potential that is tapped by ATP/ADP translocase.

History
In 1955, Siekevitz and Potter demonstrated that adenine-nucleotides were distributed in cells in two pools located in the mitochondrial and cytosolic compartments. Shortly thereafter, Pressman hypothesized that the two pools could exchange nucleotides. However, the existence of an ATP/ADP transporter was not postulated until 1964 when Bruni et al. uncovered an inhibitory effect of atractyloside on the energy-transfer system (oxidative phosphorylation) and ADP binding sites of rat liver mitochondria. Soonafter, an overwhelming amount of research was done in proving the existence and elucidating the link between ATP/ADP translocase and energy transport. cDNA of ATP/ADP translocase was sequenced for bovine in 1982 and a yeast species Saccharomyces cerevisiae in 1986 before finally Battini et al. sequenced a cDNA clone of the human transporter in 1989. The homology in the coding sequences between human and yeast ATP/ADP translocase was 47% while bovine and human sequences extended remarkable to 266 out of 297 residues, or 89.6%. In both cases, the most conserved residues lie in the ATP/ADP substrate binding pocket.

Regulation & Inhibition
Rare but severe diseases such as mitochondrial myopathies are associated with dysfunctional human ATP/ADP translocase. Mitochondrial mypoathies (MM) refer to a group of clinically and biochemically heterogenous disorders that share common features of major mitochondrial structural abnormalities in skeletal muscle. The major morphological hallmark of MM is ragged, red fibers containing peripheral and intermyofibrillar accumulations of abnormal mitochondria. In particular, autosomal dominant progressive external opthalmoplegia (adPEO) is a common disorder associated with dysfunctional ATP/ADP translocase and can induce paralysis of muscles responsible for eye movements. General symptoms are not limited to the eyes and can include exercise intolerance, muscle weakness, hearing deficit, and more. adPEO shows Mendelian inheritance patterns but is characterized by large-scale mitochondrial DNA (mtDNA) deletions. mtDNA contains few introns, or non-coding regions of DNA, which increases the likelihood of deleterious mutations. Thus, any modification of ATP/ADP translocase mtDNA can lead to a dysfunctional transporter, particularly residues involved in the binding pocket which will compromise translocase efficacy. MM is commonly associated with dysfunctional ATP/ADP translocase, but MM can be induced through many different mitochondrial abnormalities.

ATP/ADP translocase is very specifically inhibited by two families of inhibitors. The first family, which includes atractyloside (ATR) and carboxyatractyloside (CATR), binds to the ATP/ADP translocase from the matrix in lieu of ATP, causing eversion but keeping the translocase in the conformation facing the cytoplasm. In contrast, the second family, which includes bongkrekic acid (BA) and isobongkrekic acid (isoBA), binds the translocase from the cytoplasmic side in lieu of ADP, causing eversion but keeping the translocase in the conformation facing the matrix. The negatively-charged moieties of the inhibitors bind strongly with the positively-charged residues deep within the binding pocket. The high affinity (Kd in the nanomolar range) makes each inhibitor a deadly poison by obstructing cellular respiration/energy transfer to the rest of the cell.