Structure and mechanism of Na,K-ATPase: functional sites and their interactions.
The cell membrane Na,K-ATPase is a member of the P-type family of active cation transport proteins. Recently the molecular structure of the related sarcoplasmic reticulum Ca-ATPase in an E1 conformation has been determined at 2.6 A resolution. Furthermore, theoretical models of the Ca-ATPase in E2 conformations are available. As a result of these developments, these structural data have allowed construction of homology models that address the central questions of mechanism of active cation transport by all P-type cation pumps. This review relates recent evidence on functional sites of Na,K-ATPase for the substrate (ATP), the essential cofactor (Mg(2+) ions), and the transported cations (Na(+) and K(+)) to the molecular structure. The essential elements of the Ca-ATPase structure, including 10 transmembrane helices and well-defined N, P, and A cytoplasmic domains, are common to all PII-type pumps such as Na,K-ATPase and H,K-ATPases. However, for Na,K-ATPase and H,K-ATPase, which consist of both alpha- and beta-subunits, there may be some detailed differences in regions of subunit interactions. Mutagenesis, proteolytic cleavage, and transition metal-catalyzed oxidative cleavages are providing much evidence about residues involved in binding of Na(+), K(+), ATP, and Mg(2+) ions and changes accompanying E1-E2 or E1-P-E2-P conformational transitions. We discuss this evidence in relation to N, P, and A cytoplasmic domain interactions, and long-range interactions between the active site and the Na(+) and K(+) sites in the transmembrane segments, for the different steps of the catalytic cycle.
Jorgensen
Peter L
PL
Biomembrane Center, August Krogh Institute, Copenhagen University, Universitetsparken 13, 2100 Copenhagen OE, Denmark. pljorgensen@aki.ku.dk
Hakansson
Kjell O
KO
Karlish
Steven J D
SJ
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D004735:Energy Transfer / Q000502:physiology; D006801:Humans; D017434:Protein Structure, Tertiary; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000254:Sodium-Potassium-Exchanging ATPase