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Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump

Natalya U. Fedosova, Michael Habeck, Poul Nissen

10.1002/cphy.c200018

Source: Volume 12, Issue 1, January 2022

Published online: December 2021

Full Article on Wiley Online Library



Abstract

Na,K‐ATPase is an ubiquitous enzyme actively transporting Na‐ions out of the cell in exchange for K‐ions, thereby maintaining their concentration gradients across the cell membrane. Since its discovery more than six decades ago the Na‐pump has been studied extensively and its vital physiological role in essentially every cell has been established. This article aims at providing an overview of well‐established biochemical properties with a focus on Na,K‐ATPase isoforms, its transport mechanism and principle conformations, inhibitors, and insights gained from crystal structures. © 2021 American Physiological Society. Compr Physiol 11:1‐21, 2021.

Figure 1. Figure 1. Post‐Albers scheme for pumping cycle of Na,K‐ATPase.
Figure 2. Figure 2. Variety of the chemical structure of the cardiotonic steroids.
Figure 3. Figure 3. Snapshots of phosphoryl transfer reaction of the Na,K‐ATPase, revealed by crystallization with metallic fluorides. ADP:AlFx complex [PDB 3WGU, 136] mimics the Na‐occluded [Na3]E1P‐ADP state, BeFx complex [PDB 4XE5, 102] is shown with the corresponding E2P ground state [PDB 4HYT 152], both stabilized by cardiotonic steroids. [Rb2]E2:MgFx [PDB 3KDP, 181] represents product state of dephosphorylation reaction. Modified, with permission, from Kanai R, et al., 2013 136; Gregersen JL, et al., 2016 102; Laursen M, et al., 2015 152; Morth JP, et al., 2007 181.
Figure 4. Figure 4. Structure of the Na,K‐ATPase. (A) Crystal structure of the porcine Na,K‐ATPase in the Mg‐bound E2P*‐ouabain form [PDB 4HYT, 153, membrane from MemProtMD database 187]. (B) α/β/FXYD interface; (C) TGES motif shielding phosphorylaspartate in the E2P‐conformation. Mg2+ and phosphate are depicted as spheres in green and orange, respectively. Glycosylation of the β subunit, and bound ouabain (Obn) are shown in stick representation. (A) Modified, with permission, from Laursen M, et al., 2013 153; Newport TD, et al., 2019 187.
Figure 5. Figure 5. Comparison of the ion‐binding sites viewed from the cytoplasmic side of the membrane in the (A) [Na3]E1‐AlFx‐ADP [PDB 3WGU, 136] and (B) [K2]E2‐MgFx [PDB 2ZXE, 225] conformation. Residues of the ion‐binding sites are shown in stick representation with K+ colored in purple and Na+ in lime. (A) Modified, with permission, from Kanai R, et al., 2013 136. (B) Modified, with permission, from Shinoda T, et al., 2009 225.
Figure 6. Figure 6. Structures of porcine high affinity Na,K‐ATPase‐CTS complexes. (A) Crystal structure of the ouabain (Obn) complex is shown in black, bufalin (Buf) and digoxin (Dig) bound Na,K‐ATPase complexes are shown in light grey [PDB 4HYT 153, 4RES, 4RET 152]. Structures are aligned on the αM7‐10 segment highlighting the high similarity of the three complexes. (B) Comparison of the ouabain‐bound high affinity E2P (black) and low affinity [K2]E2:MgFx [light grey, PDB 3A3Y 194] conformations aligned against αM7‐10, which are not shown for clarity. Residues Q111 and D122 conferring ouabain sensitivity are shown as sticks, K and Mg ions are depicted as spheres and colored purple and green, respectively. (A) Modified, with permission, from Laursen M, et al., 2015 152; Modified, with permission, from Laursen M, et al., 2013 153. (B) Modified, with permission, from Ogawa H, et al., 2009 194.


Figure 1. Post‐Albers scheme for pumping cycle of Na,K‐ATPase.


Figure 2. Variety of the chemical structure of the cardiotonic steroids.


Figure 3. Snapshots of phosphoryl transfer reaction of the Na,K‐ATPase, revealed by crystallization with metallic fluorides. ADP:AlFx complex [PDB 3WGU, 136] mimics the Na‐occluded [Na3]E1P‐ADP state, BeFx complex [PDB 4XE5, 102] is shown with the corresponding E2P ground state [PDB 4HYT 152], both stabilized by cardiotonic steroids. [Rb2]E2:MgFx [PDB 3KDP, 181] represents product state of dephosphorylation reaction. Modified, with permission, from Kanai R, et al., 2013 136; Gregersen JL, et al., 2016 102; Laursen M, et al., 2015 152; Morth JP, et al., 2007 181.


Figure 4. Structure of the Na,K‐ATPase. (A) Crystal structure of the porcine Na,K‐ATPase in the Mg‐bound E2P*‐ouabain form [PDB 4HYT, 153, membrane from MemProtMD database 187]. (B) α/β/FXYD interface; (C) TGES motif shielding phosphorylaspartate in the E2P‐conformation. Mg2+ and phosphate are depicted as spheres in green and orange, respectively. Glycosylation of the β subunit, and bound ouabain (Obn) are shown in stick representation. (A) Modified, with permission, from Laursen M, et al., 2013 153; Newport TD, et al., 2019 187.


Figure 5. Comparison of the ion‐binding sites viewed from the cytoplasmic side of the membrane in the (A) [Na3]E1‐AlFx‐ADP [PDB 3WGU, 136] and (B) [K2]E2‐MgFx [PDB 2ZXE, 225] conformation. Residues of the ion‐binding sites are shown in stick representation with K+ colored in purple and Na+ in lime. (A) Modified, with permission, from Kanai R, et al., 2013 136. (B) Modified, with permission, from Shinoda T, et al., 2009 225.


Figure 6. Structures of porcine high affinity Na,K‐ATPase‐CTS complexes. (A) Crystal structure of the ouabain (Obn) complex is shown in black, bufalin (Buf) and digoxin (Dig) bound Na,K‐ATPase complexes are shown in light grey [PDB 4HYT 153, 4RES, 4RET 152]. Structures are aligned on the αM7‐10 segment highlighting the high similarity of the three complexes. (B) Comparison of the ouabain‐bound high affinity E2P (black) and low affinity [K2]E2:MgFx [light grey, PDB 3A3Y 194] conformations aligned against αM7‐10, which are not shown for clarity. Residues Q111 and D122 conferring ouabain sensitivity are shown as sticks, K and Mg ions are depicted as spheres and colored purple and green, respectively. (A) Modified, with permission, from Laursen M, et al., 2015 152; Modified, with permission, from Laursen M, et al., 2013 153. (B) Modified, with permission, from Ogawa H, et al., 2009 194.
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Article Title: Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump
 

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Natalya U. Fedosova, Michael Habeck, Poul Nissen. Structure and Function of Na,K‐ATPase—The Sodium‐Potassium Pump. Compr Physiol 2021, 12: 2659-2679. doi: 10.1002/cphy.c200018