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Biophys J, April 2000, p. 1765-1776, Vol. 78, No. 4

Modeling a Dehalogenase Fold into the 8-Å Density Map for Ca2+-ATPase Defines a New Domain Structure

David L. Stokes* and N. Michael Greendagger

 *Skirball Institute of Biomolecular Research, Department of Cell Biology, New York University School of Medicine, New York, New York 10016 USA, and  dagger National Institute for Medical Research, London NW7 1AA, England

Members of the large family of P-type pumps use active transport to maintain gradients of a wide variety of cations across cellular membranes. Recent structures of two P-type pumps at 8-Å resolution have revealed the arrangement of transmembrane helices but were insufficient to reveal the architecture of the cytoplasmic domains. However, recent proposals of a structural homology with a superfamily of hydrolases offer a new basis for modeling these domains. In the current work, we have extended the sequence comparison for the superfamily and delineated domains in the 8-Å density map of Ca2+-ATPase. The homology suggests a new domain structure for Ca2+-ATPase and, specifically, that the phosphorylation domain adopts a Rossman fold. Accordingly, the atomic structure of L-2 haloacid dehalogenase has been fitted into the relevant domain of Ca2+-ATPase. The resulting model suggests the existence of two ATP sites at the interface between two domains. Based on this new model, we are able to reconcile numerous results of mutagenesis and chemical cross-linking within the catalytic domains. Furthermore, we have used the model to predict the configuration of Mg·ATP at its binding site. Based on this prediction, we propose a mechanism, involving a change in Mg2+ liganding, for initiating the domain movements that couple sites of ion transport to ATP hydrolysis.

Biophys J, April 2000, p. 1765-1776, Vol. 78, No. 4
© 2000 by the Biophysical Society   0006-3495/00/04/1765/12  $2.00


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