Article

Function, structure and regulation of the vacuolar (H+)-ATPases

Department of Physiology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
Archives of Biochemistry and Biophysics (Impact Factor: 3.02). 09/2008; 476(1):33-42. DOI: 10.1016/j.abb.2008.03.025
Source: PubMed

ABSTRACT

The vacuolar ATPases (or V-ATPases) are ATP-driven proton pumps that function to both acidify intracellular compartments and to transport protons across the plasma membrane. Intracellular V-ATPases function in such normal cellular processes as receptor-mediated endocytosis, intracellular membrane traffic, prohormone processing, protein degradation and neurotransmitter uptake, as well as in disease processes, including infection by influenza and other viruses and killing of cells by anthrax and diphtheria toxin. Plasma membrane V-ATPases are important in such physiological processes as urinary acidification, bone resorption and sperm maturation as well as in human diseases, including osteopetrosis, renal tubular acidosis and tumor metastasis. V-ATPases are large multi-subunit complexes composed of a peripheral domain (V(1)) responsible for hydrolysis of ATP and an integral domain (V(0)) that carries out proton transport. Proton transport is coupled to ATP hydrolysis by a rotary mechanism. V-ATPase activity is regulated in vivo using a number of mechanisms, including reversible dissociation of the V(1) and V(0) domains, changes in coupling efficiency of proton transport and ATP hydrolysis and changes in pump density through reversible fusion of V-ATPase containing vesicles. V-ATPases are emerging as potential drug targets in treating a number of human diseases including osteoporosis and cancer.

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    • "The Vacuole-type ATPases (V o V 1 ) are found in many organisms and are involved in a variety of physiological processes[[1,4]) produce ATP using the energy stored in a transmembrane electrochemical proton gradient[3,5], while the V o V 1 of some anaerobic bacteria, such as Enterococcus hirae, function as a sodium pump[6]. The V o V 1 and F o F 1 ATPases/synthases are evolutionarily related and share a rotary mechanism to perform their specific functions[3,789. The basic structures of the ATPases/synthases are conserved among species123. "
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    ABSTRACT: Vacuolar type rotary H+-ATPases (VoV1) couple ATP synthesis/hydrolysis by V1 with proton translocation by Vo via rotation of a central rotor apparatus composed of the V1-DF rotor shaft, a socket-like Vo-C (eukaryotic Vo-d) and the hydrophobic rotor ring. Reconstitution experiments using subcomplexes revealed a weak binding affinity of V1-DF to Vo-C despite the fact that torque needs to be transmitted between V1-DF and Vo-C for the tight energy coupling between V1 and Vo. Mutation of a short helix at the tip of V1-DF caused intramolecular uncoupling of VoV1, suggesting that proper fitting of the short helix of V1-D into the socket of Vo-C is required for tight energy coupling between V1 and Vo. To account for the apparently contradictory properties of the interaction between V1-DF and Vo-C (weak binding affinity but strict requirement for torque transmission), we propose a model in which the relationship between V1-DF and Vo-C corresponds to that between a slotted screwdriver and a head of slotted screw. This model is consistent with our previous result in which the central rotor apparatus is not the major factor for the association of V1 with Vo (Kishikawa and Yokoyama, J Biol Chem. 2012 24597-24603).
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    • "Most fungal V-ATPase subunits are encoded by a single gene; the Voa subunit is the only subunit encoded by two isoforms. Mammalian V-ATPases are strikingly different, with seven different subunits displaying isoform variation (Jefferies et al., 2008; Figure 1). This drastic difference between fungi and mammals could be exploited for fungal-specific drug development. "
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    • "V-ATPases are highly conserved ATP-dependent proton pumps that play a universal role as pH regulators in intracellular acidic organelles of eukaryotic cells. They form multi-subunit complexes assembled in two subdomains: the Vo membrane domain, which is responsible for proton transport across membranes and is comprised of the subunits a, d, c, c″, and e; and the V1 cytoplasmic domain, which is responsible for ATP hydrolysis and is made up of 8 subunit types, designated as A to H. Intracellular V-ATPases play essential roles in receptor-mediated endocytosis, vesicular trafficking between organelles, membrane fusion, protein degradation and autophagy123. In addition to their role in intracellular compartments, V-ATPases can also pump protons across the plasma membrane, thus acidifying the extracellular medium. "
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    ABSTRACT: Vacuolar-type H(+) ATPases (V-ATPases) are multimeric protein complexes that play a universal role in the acidification of intracellular compartments in eukaryotic cells. We have isolated the recessive medaka mutation tintachina (tch), which carries an inactivating modification of the conserved glycine residue (G75R) of the proton pump subunit atp6v1Ba/vatB1. Mutant embryos show penetrant pigmentation defects, massive brain apoptosis and lethality before hatching. Strikingly, an equivalent mutation in atp6v1B1 (G78R) has been reported in a family of patients suffering from distal renal tubular acidosis (dRTA), a hereditary disease that causes metabolic acidosis due to impaired kidney function. This poses the question as to how molecularly identical mutations result in markedly different phenotypes in two vertebrate species. Our work offers an explanation for this phenomenon. We propose that, after successive rounds of whole-genome duplication, the emergence of paralogous copies allowed the divergence of the atp6v1B cis-regulatory control in different vertebrate groups.
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