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First published online January 31, 2006
Journal of Experimental Biology 209, 577-589 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02014
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The V-type H+ ATPase: molecular structure and function, physiological roles and regulation

Klaus W. Beyenbach1,* and Helmut Wieczorek2

1 Department of Biomedical Sciences, VRT 8004, Cornell University, Ithaca, NY 14853, USA
2 Department of Biology/Chemistry, University of Osnabrück, 49069 Osnabrück, Germany


Figure 1
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  		Fig. 1. Electron micrographs of `studs', the globular headpieces of the V1 complex of the V-type H+ ATPase. (a) Stereoelectron micrograph of a vesicle from the apical region of a mitochondria-rich cell after rapid freezing and freeze-drying of apical membrane segments of toad urinary bladder (courtesy of D. Brown, Boston). (b) Negative stained electron micrograph of a vesicle after purification of goblet cell apical membranes from the midgut of the tobacco hornworm (courtesy of M. Huss and H. Wieczorek, Osnabrück). The diameter of `studs' (portasomes) is approximately 10 nm. The average density is about 16 800 studs µm-2 of membrane in the toad urinary bladder (Brown et al., 1987Go) and about 5000 µm-2 in the tobacco hornworm.

 

Figure 2
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  		Fig. 2. Model of the V-type H+ ATPase expressed in a eukaryotic cell membrane. (A) Molecular model. The peripheral V1 complex consists of eight different subunits identified with capital letters A-H. Subunit G exists as the dimer G2. The integral membrane V0 complex consists of at least four different subunits identified with small letters (a,c,d,e). Subunit c and its isoforms c' and c'' form a H+-binding rotor ring. Actin binds to subunits B (Holliday et al., 2000Go) and C (Vitavska et al., 2003Go). (B) Mechanistic model. V0 and V1 complexes are joined by a central rotating shaft (subunits D,F) and a peripheral stationary shaft (subunits C,E,G,H,a). The central shaft of the V1 complex and the c-ring of the V0 complex form the rotor (red). The remainder is considered the stator (grey). Hydrolysis of ATP brings about rotation of the central shaft together with the c-ring of the V0 complex. Subunit a hypothetically provides two H+ half channels that are offset. Rotation of the c-ring conveys H+ from the inner half channel to the outer half channel via an intermediary H+ binding step to one subunit c. The pleomacrolides bafilomycin and concanomycin, as well as the recently discovered macrolactone archazolid, are highly specific inhibitors that bind to the c subunits in the V0 complex (Huss et al., 2002Go; Huss et al., 2005Go). Adapted from various sources (Inoue and Forgac, 2005Go; Murata et al., 2005Go; Wilkens et al., 2005Go).

 

Figure 3
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  		Fig. 3. Utility of the V-type H+ ATPase expressed in endosomal membranes. Large transmembrane H+ electrochemical potentials generated by the V-type H+ ATPase drive the electrophoretic uptake of malate in vacuoles of plants (A), electrophoretic Cl- transport across endocytotic membranes via the Cl-/H+ antiporter ClC-5 (B), and the uptake of the neurotransmitter serotonin (S+) in synaptic vesicles via VMAT, a member of the SLC18 family of solute-linked-carriers (C). See www.bioparadigms.og/slc/menu.asp for the HUGO classification of solute-linked-carriers.

 

Figure 4
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  		Fig. 4. Utility of the V-type H+ ATPase expressed in plasma membranes. (A) Coupling of proton secretion to K+ secretion via electrogenic 2H+/K+ antiport in apical membranes of goblet cells in insect midgut (Azuma et al., 1995Go). (B) Secretion of strong acid across the ruffled border membrane (apical membrane) into the lacunar space of osteoclasts, serving the acid digestion of bone (Chatterjee et al., 1992Go; Cleiren et al., 2001Go). (C) Coupling of proton secretion to oligopeptide absorption in the apical brush border membrane of the renal proximal tubule (Lee and Kim, 2004Go; Wagner et al., 2004Go).

 

Figure 5
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  		Fig. 5. The V-type H+ ATPase powers transepithelial NaCl and KCl secretion in Malpighian tubules of the yellow fever mosquito. Only conductive transport pathways are shown to illustrate diverse voltage-dependent transport mechanisms driven by the V-type H+ ATPase located at the apical membrane. Intraepithelial current generated by the proton pump is carried by H+ across the apical membrane, by Cl- through the paracellular pathway (septate junctions, sj), and by K+ and Na+ across the basolateral membrane. Under control conditions, K+ channels account for as much as 64% of the conductance of the basolateral membrane (Beyenbach and Masia, 2002Go). Claudin-like proteins are hypothesized to define the Cl- selectivity of the paracellular, septate junctional pathway (Beyenbach, 2003Go).

The 2H+/cat+ antiporter in the apical membrane remains to be identified. Mosquito natriuretic peptide and its second messenger cyclic AMP decrease the resistance to Na+ entry across the basolateral membrane (Beyenbach, 2001Go). The diuretic peptide leucokinin decreases the resistance of the paracellular pathway for Cl- (Beyenbach, 2003Go). Ep, electromotive force of the V-type H+ ATPase; R, resistance; I, current; p, pump, cat+, cation. Ep and Rp form a proton current generator.

 

Figure 6
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  		Fig. 6. Dissociation of the V-type H+ ATPase into V1 and V0 complexes. (A) The intact holoenzyme hydrolyzes ATP, transports H+, and generates voltage across the membrane; (B) intestinal inactivity during molt or starvation in caterpillars and glucose deprivation in yeasts causes the holoenzyme to dissociate. Concomitantly, ATP hydrolysis and proton transport collapse and membrane voltage goes to zero. (Adapted from Vitavska, 2005Go.)

 

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