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9.A.6 The ATP Exporter (ATP-E) Family

External nucleotides in eukaryotes are signalling molecules interacting with two families of purinergic receptors in animals, P2Y (G protein coupled) and P2X (TC #1.A.7). The former proteins (P2Y1 and P2Y2-like mitochondrial receptor in humans) regulate mitochondrial Ca2+ transport (Belous et al., 2006). ATP can be released by more than one mechanism (1) by exocytosis and (2) possibly by ATP channels regulated by tyrosine and Rho kinases. ATP release can be constitutive or mechanically induced, but it is not known which is mediated by vesicular fusion or by direct movement of ATP across the membrane.

In the ER and Golgi, ATP:ADP exchange processes have been characterized. The Mcd4 protein of Saccharomyces cerevisiae (Maneesri et al., 2005) has been implicated in ATP release from the cell cytoplasm into the Golgi and endoplasmic reticulum lumen as well as the extracellular medium (Zhong et al., 2003). Mcd4-mediated ATP release occurs through the membrane-trafficking pathway initiated by ATP uptake into the Golgi. Both the uptake and release proved to depend on the activity of the vacuolar ATPase.

Homologues of Mcd4 are found in animals, fungi and plants, and possibly just one full length homologue is found in each organism, including those with fully sequenced genomes. The proteins have an N-terminal TMS, a hydrophilic domain of about 450 residues, and a second transmembrane domain. Mcd4 is required for GPI anchor synthesis. In animals, the homologues are called phosphatidyl inositol glycans, class N. They are usually between 800 and 920 residues in length.

The proposed transport reaction catalyzed by Mcd4 is:

ATP (in) → ATP (out)

References associated with 9.A.6 family:

Belous, A.E., C.M. Jones, A. Wakata, C.D. Knox, I.B. Nicoud, J. Pierce, and R.S. Chari. (2006). Mitochondrial calcium transport is regulated by P2Y(1)- and P2Y(2)-like mitochondrial receptors. J. Cell. Biochem. 99: 1165-1174. 16795051
Maneesri, J., M. Azuma, Y. Sakai, K. Igarashi, T. Matsumoto, H. Fukuda, A. Kondo, and H. Ooshima. (2005). Deletion of MCD4 involved in glycosylphosphatidylinositol (GPI) anchor synthesis leads to an increase in β-1,6-glucan level and a decrease in GPI-anchored protein and mannan levels in the cell wall of Saccharomyces cerevisiae. J. Biosci. Bioeng. 99: 354-360. 16233801
Zhong, X., R. Malhotra, and G. Guidotti. (2003). ATP uptake in the Golgi and extracellular release require Mcd4 protein and the vacuolar H+-ATPase. J. Biol. Chem. 278: 33436-33444. 12807869