Family 3.A.3 - The P-Type ATPase Superfamily       

Family ID: 52651

Nearly all of the members of this superfamily, found in bacteria, archaea and eukaryotes, catalyze cation uptake and/or efflux driven by ATP hydrolysis. Clustering on the phylogenetic tree is usually in accordance with specificity for the transported ion(s). Most of these protein complexes are multisubunit with a large subunit serving the primary ATPase and ion translocation functions. In eukaryotes, they are present in the plasma membranes or endoplasmic reticular membranes. In prokaryotes, they are localized to the cytoplasmic membranes. Gastric H+-translocating ATPases comprise a subgroup of the larger and more diverse Na+/K+ ATPase subfamily (subfamily #1). Ca2+ ATPases of eukaryotes comprise a very diverse subfamily (subfamily #2) including both plasma membrane and sarcoplasmic reticular types. H+-translocating P-type ATPases of plant and fungi comprise their own subfamily (subfamily #3). Distinct bacterial enzymes specific for K+ or Mg2+ (uptake), Ca2+, Ag2+, Zn2+, Co2+, Pb2+, Ni2+, and/or Cd2+ (efflux) and Cu2+ or Cu+ (uptake or efflux, depending on the system) have been characterized, and each of these enzymes comprises a distinct subfamily. Cu2+ or Cu+-translocating ATPases from bacteria and animals cluster together, and some of these may also transport Ag+.

Many eukaryotic P-type ATPases are homodimers of the catalytic subunit that hydrolyzes ATP, contains the aspartyl phosphorylation site and catalyzes ion transport. The Na+, K+-ATPases, the Ca2+-ATPases and the (fungal) H+-ATPases of higher organisms exhibit 10 transmembrane a-helical spanners (TMSs), some of them highly tilted. However, additional subunits that appear to lack catalytic activity may be present in the ATPase complex. For example, the 10 TMS catalytic a-subunit of the Na+, K+-ATPase of animals is tightly complexed to the 1 TMS b-subunit and the tissue-specific, regulatory, 1 TMS g-subunit. The b-subunit, which may influence the activity of the a-subunit, probably functions to facilitate proper insertion of the a-subunit into the membrane, to allow proper targeting to a subcellular membrane site in post-translational processing, and to stabilize the catalytic subunit. The b-subunit can therefore be considered to be an auxiliary protein of the Na+, K+-ATPase catalytic subunit. The g-subunit of the Na+, K+-ATPase has been reported to influence kinetic parameters and is homologous to a family of pore-forming peptides, the peptides of the phospholemman family (TC #1.A.27). Several P-type ATPases also depend on small proteolipids, the functions of which are uncertain.

Considerable evidence is available showing that animals have a Cl- translocating, Cl- stimulating P-type ATPase. Although extensive biochemical data are available, the protein sequence of any one such Cl- ATPase has not yet been determined (Gerencser, 1993; Inagaki et al., 1996; Zeng et al., 1999). Evidence for mammalian iron-inducible, iron-transporting ATPases is also available (Baranano et al., 2000). Finally bacterial Na+-transporting P-type ATPases probably exist (Ueno et al., 2000), thus the breadth of substrates transported by P-type ATPases is likely to be much greater than currently recognized.

The stoichiometries of transport are sometimes known and complex. In the case of the Na+, K+ ATPases, 3 Na+ are exchanged for 2 K+ per ATP molecule hydrolyzed. The gastric H+-translocating ATPases replace H+ for Na+. The Ca2+ ATPase may catalyze Ca2+-K+ antiport. A single organism may possess multiple isoforms of these enzymes. Some members of the P-type ATPase family have been reported to flip phospholipids from one bilayer of the membrane to the other.