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Gastric H+,K+‐ATPase

Jai Moo Shin, Keith Munson, George Sachs

10.1002/cphy.c110010

Source: Volume 1, Issue 4, October 2011

Published online: October 2011

Full Article on Wiley Online Library



Abstract

The gastric H+,K+‐ATPase is responsible for gastric acid secretion. This ATPase is composed of two subunits, the catalytic α subunit and the structural β subunit. The α subunit with molecular mass of about 100 kDa has 10 transmembrane domains and is strongly associated with the β subunit with a single transmembrane segment and a peptide mass of 35 kDa. Its three‐dimensional structure is based on homology modeling and site‐directed mutagenesis resulting in a proton extrusion and K+ reabsorption model. There are three conserved H3O+‐binding sites in the middle of the membrane domain and H3O+ secretion depends on a conformational change involving Lys791 insertion into the second H3O+ site enclosed by E795, E820, and D824 that allows export of protons at a concentration of 160 mM. K+ countertransport involves binding to this site after the release of protons with retrograde displacement of Lys791 and then K+ transfer to E343 and exit to the cytoplasm. This ATPase is the major therapeutic target in treatment of acid‐related diseases and there are several known luminal inhibitors allowing analysis of the luminal vestibule. One class contains the acid‐activated covalent, thiophilic proton pump inhibitors, the most effective of current acid‐suppressive drugs. Their binding sites and trypsinolysis allowed identification of all ten transmembrane segments of the ATPase. In addition, various K+‐competitive inhibitors of the ATPase are being developed, with the advantage of complete and rapid inhibition of acid secretion independent of pump activity and allowing further refinement of the structure of the luminal vestibule of the E2 form of this ATPase. © 2011 American Physiological Society. Compr Physiol 1:2141‐2153, 2011.

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Figure 1. Figure 1.

The structure of the gastric H+,K+‐ATPase. The modeled three‐dimensional structure of the H+,K+‐ATPase, HKzxe based on the Na+,K+‐ATPase in the E2P state. The α subunit has three lobes, N (ATP binding), P (phosphorylation), and A (activation) domains in the cytoplasmic domain, and ten transmembrane segments in the membrane domain. The gastric β subunit has short cytoplasmic region, one transmembrane segment, and a heavily glycosylated extracellular region. In this model, the backbone of protein with carbohydrate attached Asn sites is shown. Amino acid sequence number is based on pig H+,K+‐ATPase.
Figure 2. Figure 2.

The catalytic cycle of the gastric H+,K+‐ATPase. A hydronium ion binds to the cytoplasmic surface of the enzyme, and MgATP phosphorylates the protein at Asp386 to form the first ion transport intermediate in the E1P form. The E1P form then converts by a conformational change to the second ion transport form, E2P, with the ion site now exposed to the exterior and hydronium is released at pH ∼1.0. To this form, K+ binds from the outside surface to the same region from which the hydronium was released, and the enzyme dephosphorylates, and then K+ is trapped within the membrane domain in the occluded form (and a similar form is postulated for the hydronium in the outward step of the cycle). The K+ is then deoccluded allowing reformation of the E1 form of the enzyme with the ion site now again facing the cytoplasm and K+ is displaced when ATP is bound. In this model, the naked H+ is used instead of the hydronium ion (H3O+). This model reflects a stoichiometry of 1H/1K/1ATP.
Figure 3. Figure 3.

A model of the H+,K+ ion exchange at acidic luminal pH based on the three‐dimensional structure of the srCa‐ATPase. In panel 1 the 3 hydronium ion‐binding sites at the carboxylates in TM 5, 6 and TM3 with the exported ion at acidic pH outlined in yellow. In panel 2 after phosphorylation, lys791 displaces the hydronium from site 2 in the E1P form (arrow). Then in panel 3 K+ binds to site 2 displacing lys791 generating the E2P form and in panel 4 K+ moves into site 3 allowing exit to the cytoplasm along TM3.
Figure 4. Figure 4.

SCH28080‐bound E2P structure of the gastric H+,K+‐ATPase analyzed at 7 Å resolution. (A) The structure of the H+,K+‐ATPase showing cytoplasmic‐side up. Surface represents the EM density map with superimposed homology model of H+,K+‐ATPase (ribbon). Bound SCH28080 at the luminal cavity, and ADP at the N domain are shown as sticks. A wheat box indicates approximate location of the lipid bilayer. Color code: A domain, blue; P domain, green; N domain, yellow; TM domain, light blue (surface); and β subunit, red. Color for the TM helices of the homology model gradually changes from M1 (blue) to M10 (red). (B) Conformational change of the cytoplasmic domain seen from the top. Surface shows EM density map of (SCH)E2BeF and orange mesh represents E2AlF EM map of the gastric H+,K+‐ATPase. The intersubunit interaction between the P domain and the N‐terminal tail of the β subunit is observed in E2AlF structure, but not present in (SCH)E2BeF structure. White arrows indicate observation of the conformational changes during E2AlF → (SCH)E2BeF transition. This figure is cited, with permission, from the work of Abe et al. 1 and is similar to the homology model of the H+,K+‐ATPase shown above and below.
Figure 5. Figure 5.

K+ pathway in the H+,K+‐ATPase. The image illustrates the entry path for K+ (illustrated as a series of violet spheres) between M4, M5, M6, and M8 in the E2P conformation as determined by molecular dynamics simulation (M3 in the foreground is omitted for clarity) 35,50. The arrival of K+ at the top of this path is predicted to destabilize the interaction of K791 with E820 and E795, and initiate the conformational changes leading to release of phosphate at the active site and conversion back to E1.
Figure 6. Figure 6.

Proposed K+ pathway through the pump srCa‐ATPase homology model. Red to pink is area of restriction including the occlusion site. White to blue less occlusion. Arrows highlight entry and exit pathways for K+.
Figure 7. Figure 7.

Proton pump inhibitors.
Figure 8. Figure 8.

The mechanism of activation of the PPIs shown in general structural form. The substituent R1, R2, R3, and R4 of the general structure (Bz‐Py) represent a substituent chosen from hydrogen, methoxy, methyl, and substituted alkoxy group. Top part shows the protonation of the pyridine ring and the second row of structures shows protonation also of the benzimidazole ring. The bis‐protonated forms are in equilibrium with the protonated benzimidazole and unprotonated pyridine. In brackets is shown the mechanism of activation whereby the 2C of the protonated benzimidazole reacts with the unprotonated fraction of the pyridine moiety that results in rearrangement to a permanent cationic tetracyclic sulfenic acid which in aqueous solute dehydrates to form a cationic sulfenamide. Either of these thiophilic species can react with the enzyme to form disulfides with one or more enzyme cysteines accessible from the luminal surface of the enzyme.
Figure 9. Figure 9.

The amino acids lining the luminal entrance (vestibule) to the ion‐binding sites of the H+,K+‐ATPase that is the basis for docking pyrrolo‐pyridines suggesting critical amino acid residues responsible for high affinity and slow dissociation.
Figure 10. Figure 10.

Acid pump antagonists.
Figure 11. Figure 11.

The vestibule structure predicted for bound TAK‐438. Selected amino acids in the binding region are predicted to affect binding (white, bold). Also shown is H bonding to E795 ‐COO− and ‐C=O and to Y799.


Figure 1.

The structure of the gastric H+,K+‐ATPase. The modeled three‐dimensional structure of the H+,K+‐ATPase, HKzxe based on the Na+,K+‐ATPase in the E2P state. The α subunit has three lobes, N (ATP binding), P (phosphorylation), and A (activation) domains in the cytoplasmic domain, and ten transmembrane segments in the membrane domain. The gastric β subunit has short cytoplasmic region, one transmembrane segment, and a heavily glycosylated extracellular region. In this model, the backbone of protein with carbohydrate attached Asn sites is shown. Amino acid sequence number is based on pig H+,K+‐ATPase.



Figure 2.

The catalytic cycle of the gastric H+,K+‐ATPase. A hydronium ion binds to the cytoplasmic surface of the enzyme, and MgATP phosphorylates the protein at Asp386 to form the first ion transport intermediate in the E1P form. The E1P form then converts by a conformational change to the second ion transport form, E2P, with the ion site now exposed to the exterior and hydronium is released at pH ∼1.0. To this form, K+ binds from the outside surface to the same region from which the hydronium was released, and the enzyme dephosphorylates, and then K+ is trapped within the membrane domain in the occluded form (and a similar form is postulated for the hydronium in the outward step of the cycle). The K+ is then deoccluded allowing reformation of the E1 form of the enzyme with the ion site now again facing the cytoplasm and K+ is displaced when ATP is bound. In this model, the naked H+ is used instead of the hydronium ion (H3O+). This model reflects a stoichiometry of 1H/1K/1ATP.



Figure 3.

A model of the H+,K+ ion exchange at acidic luminal pH based on the three‐dimensional structure of the srCa‐ATPase. In panel 1 the 3 hydronium ion‐binding sites at the carboxylates in TM 5, 6 and TM3 with the exported ion at acidic pH outlined in yellow. In panel 2 after phosphorylation, lys791 displaces the hydronium from site 2 in the E1P form (arrow). Then in panel 3 K+ binds to site 2 displacing lys791 generating the E2P form and in panel 4 K+ moves into site 3 allowing exit to the cytoplasm along TM3.



Figure 4.

SCH28080‐bound E2P structure of the gastric H+,K+‐ATPase analyzed at 7 Å resolution. (A) The structure of the H+,K+‐ATPase showing cytoplasmic‐side up. Surface represents the EM density map with superimposed homology model of H+,K+‐ATPase (ribbon). Bound SCH28080 at the luminal cavity, and ADP at the N domain are shown as sticks. A wheat box indicates approximate location of the lipid bilayer. Color code: A domain, blue; P domain, green; N domain, yellow; TM domain, light blue (surface); and β subunit, red. Color for the TM helices of the homology model gradually changes from M1 (blue) to M10 (red). (B) Conformational change of the cytoplasmic domain seen from the top. Surface shows EM density map of (SCH)E2BeF and orange mesh represents E2AlF EM map of the gastric H+,K+‐ATPase. The intersubunit interaction between the P domain and the N‐terminal tail of the β subunit is observed in E2AlF structure, but not present in (SCH)E2BeF structure. White arrows indicate observation of the conformational changes during E2AlF → (SCH)E2BeF transition. This figure is cited, with permission, from the work of Abe et al. 1 and is similar to the homology model of the H+,K+‐ATPase shown above and below.



Figure 5.

K+ pathway in the H+,K+‐ATPase. The image illustrates the entry path for K+ (illustrated as a series of violet spheres) between M4, M5, M6, and M8 in the E2P conformation as determined by molecular dynamics simulation (M3 in the foreground is omitted for clarity) 35,50. The arrival of K+ at the top of this path is predicted to destabilize the interaction of K791 with E820 and E795, and initiate the conformational changes leading to release of phosphate at the active site and conversion back to E1.



Figure 6.

Proposed K+ pathway through the pump srCa‐ATPase homology model. Red to pink is area of restriction including the occlusion site. White to blue less occlusion. Arrows highlight entry and exit pathways for K+.



Figure 7.

Proton pump inhibitors.



Figure 8.

The mechanism of activation of the PPIs shown in general structural form. The substituent R1, R2, R3, and R4 of the general structure (Bz‐Py) represent a substituent chosen from hydrogen, methoxy, methyl, and substituted alkoxy group. Top part shows the protonation of the pyridine ring and the second row of structures shows protonation also of the benzimidazole ring. The bis‐protonated forms are in equilibrium with the protonated benzimidazole and unprotonated pyridine. In brackets is shown the mechanism of activation whereby the 2C of the protonated benzimidazole reacts with the unprotonated fraction of the pyridine moiety that results in rearrangement to a permanent cationic tetracyclic sulfenic acid which in aqueous solute dehydrates to form a cationic sulfenamide. Either of these thiophilic species can react with the enzyme to form disulfides with one or more enzyme cysteines accessible from the luminal surface of the enzyme.



Figure 9.

The amino acids lining the luminal entrance (vestibule) to the ion‐binding sites of the H+,K+‐ATPase that is the basis for docking pyrrolo‐pyridines suggesting critical amino acid residues responsible for high affinity and slow dissociation.



Figure 10.

Acid pump antagonists.



Figure 11.

The vestibule structure predicted for bound TAK‐438. Selected amino acids in the binding region are predicted to affect binding (white, bold). Also shown is H bonding to E795 ‐COO− and ‐C=O and to Y799.

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Further Reading
 1. Ogawa H, Shinoda T, Cornelius F, Toyoshima C. Crystal structure of the sodium‐potassium pump (Na+,K+‐ATPase) with bound potassium and ouabain. Proc Natl Acad Sci U S A 106: 13742‐13742, 2009.
 2. Shin JM, Munson K, Vagin O, Sachs G. The gastric HK‐ATPase: Structure, function, and inhibition. Pflugers Arch 457: 609‐609, 2009.
 3. Shin JM, Vagin O, Munson K, Kidd M, Modlin IM, Sachs G. Molecular mechanisms in therapy of acid‐related diseases. Cell Mol Life Sci 65: 264‐264, 2008.
 4. Shinoda T, Ogawa H, Cornelius F, Toyoshima C. Crystal structure of the sodium‐potassium pump at 2.4 Å resolution. Nature 459: 446‐446, 2009.
 5. Vagin O, Tokhtaeva E, Yakubov I, Shevchenko E, Sachs G. Inverse correlation between the extent of N‐glycan branching and intercellular adhesion in epithelia. Contribution of the Na,K‐ATPase beta1 subunit. J Biol Chem 283: 2192‐2192, 2008.

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Article Title: Gastric H+,K+‐ATPase
 

How to Cite

Jai Moo Shin, Keith Munson, George Sachs. Gastric H+,K+‐ATPase. Compr Physiol 2011, 1: 2141-2153. doi: 10.1002/cphy.c110010