[1] P-type ATPases are α-helical bundle primary transporters named based upon their ability to catalyze auto- (or self-) phosphorylation (hence P) of a key conserved aspartate residue within the pump and their energy source, adenosine triphosphate (ATP).

Most members of this transporter superfamily catalyze cation uptake and/or efflux, however one subfamily, the flippases, (TC# 3.A.3.8) is involved in flipping phospholipids to maintain the asymmetric nature of the biomembrane.

The first P-type ATPase to be crystallized was SERCA1a, a sarco(endo)plasmic reticulum Ca2+-ATPase of fast twitch muscle from adult rabbit.

Common for all P-type ATPases is a core of 6 transmembrane-spanning segments (also called the 'transport (T) domain'; M1-M6 in SERCA), that harbors the binding sites for the translocated ligand(s).

Varying among P-type ATPase is the additional number of transmembrane-spanning segments (also called the 'support (S) domain', which between subfamilies ranges from 2 to 6.

These two parts assemble into a seven-strand parallel β-sheet with eight short associated a-helices, forming a Rossmann fold.

[9] The phylogenetic analysis grouped the proteins independent of the organism from which they are isolated and showed that the diversification of the P-type ATPase family occurred prior to the separation of eubacteria, archaea, and eucaryota.

Metal binding to transmembrane metal-binding sites (TM-MBS) in Cu+-ATPases is required for enzyme phosphorylation and subsequent transport.

[11] Wu et al. (2008) have determined structures of two constructs of the Cu (CopA) pump from Archaeoglobus fulgidus by cryoelectron microscopy of tubular crystals, which revealed the overall architecture and domain organization of the molecule.

They localized its N-terminal MBD within the cytoplasmic domains that use ATP hydrolysis to drive the transport cycle and built a pseudoatomic model by fitting existing crystallographic structures into the cryoelectron microscopy maps for CopA.

[12] In the Archaeoglobus fulgidus CopA (TC# 3.A.3.5.7), invariant residues in helixes 6, 7 and 8 form two transmembrane metal binding sites (TM-MBSs).

Archetypical Cu+-efflux pumps responsible for Cu+ tolerance, like the Escherichia coli CopA, have turnover rates ten times higher than those involved in cuproprotein assembly (or alternative functions).

This explains the incapability of the latter group to significantly contribute to the metal efflux required for survival in high copper environments.

These pumps have two Ca2+ ion binding sites and are often regulated by inhibitory accessory proteins having a single trans-membrane spanning segment (e.g.phospholamban and sarcolipin.

These pumps have a single Ca2+ ion binding site and are located in secretory vesicles (animals) or the vacuolar membrane (fungi).

Starting in the E1/E2 state, the reaction cycle begins as the enzyme releases 1-3 protons from the cation-ligating residues, in exchange for cytoplasmic Ca2+-ions.

This movement of the A domain exerts a downward push on M3-M4 and a drag on M1-M2, forcing the pump to open at the luminal side and forming the E2P state.

[15] The nucleotide binding (N) and β-sheet (β) domains are highly mobile, with N flexibly linked to P, and β flexibly linked to M. Modeling of the fungal H+ ATPase, based on the structures of the Ca2+ pump, suggested a comparable 70º rotation of N relative to P to deliver ATP to the phosphorylation site.

[18] Anthonisen et al. (2006) characterized the kinetics of the partial reaction steps of the transport cycle and the binding of the phosphoryl analogs BeF, AlF, MgF, and vanadate in mutants with alterations to conserved TGES loop residues.

(TC# 3.A.3.1) The X-ray crystal structure at 3.5 Å resolution of the pig renal Na+/K+-ATPase has been determined with two rubidium ions bound in an occluded state in the transmembrane part of the α-subunit.

[20] Several of the residues forming the cavity for rubidium/potassium occlusion in the Na+/K+-ATPase are homologous to those binding calcium in the Ca2+-ATPase of the sarco(endo)plasmic reticulum.

The carboxy terminus of the α-subunit is contained within a pocket between transmembrane helices and seems to be a novel regulatory element controlling sodium affinity, possibly influenced by the membrane potential.

P3A ATPases (or Type IIIA) contain the plasma membrane H+-ATPases from prokaryotes, protists, plants and fungi.

The transmembrane domain reveals a large cavity, which is likely to be filled with water, located near the middle of the membrane plane where it is lined by conserved hydrophilic and charged residues.

[27][28] In addition to the subfamilies of P-type ATPases listed above, several prokaryotic families of unknown function have been identified.

[29] The Transporter Classification Database provides a representative list of members of the P-ATPase superfamily, which as of early 2016 consisting of 20 families.

[10][30] Chan et al., (2010) conducted an equivalent but more extensive analysis of the P-type ATPase Superfamily in Prokaryotes and compared them with those from Eukaryotes.

In some cases, gene fusion events created P-type ATPases covalently linked to regulatory catalytic enzymes.

Chan et al. (2010) suggested that in prokaryotes and some unicellular eukaryotes, the primary function of P-type ATPases is protection from extreme environmental stress conditions.

The classification of P-type ATPases of unknown function into phylogenetic families provides guides for future molecular biological studies.