The Journal of Membrane Biology

, Volume 195, Issue 2, pp 93–108 | Cite as

Identification of Ion-Selectivity Determinants in Heavy-Metal Transport P1B-type ATPases

  • J. M. ArgüelloEmail author


P1B-type ATPases transport a variety of metals (Cd2+, Zn2+, Pb2+, Co2+, Cu2+, Ag+, Cu+) across biomembranes. Characteristic sequences CP[C/H/S] in transmembrane fragment H6 were observed in the putative transporting metal site of the founding members of this subfamily (initially named CPx-ATPases). In spite of their importance for metal homeostasis and biotolerance, their mechanisms of ion selectivity are not understood. Studies of better-characterized PII-type ATPases (Ca-ATPase and Na,K-ATPase) have identified three transmembrane segments that participate in ion binding and transport. Testing the hypothesis that metal specificity is determined by conserved amino acids located in the equivalent transmembrane segments of P1B-type ATPases (H6, H7, and H8), 234 P1B-ATPase protein sequences were analyzed. This showed that although H6 contains characteristic CPX or XPC sequences, conserved amino acids in H7 and H8 provide signature sequences that predict the metal selectivity in each of five P1B-ATPase subgroups identified. These invariant amino acids contain diverse side chains (thiol, hydroxyl, carbonyl, amide, imidazolium) that can participate in transient metal coordination during transport and consequently determine the particular metal selectivity of each enzyme. Each subgroup shares additional structural characteristics such as the presence (or absence) of particular amino-terminal metal-binding domains and the number of putative transmembrane segments. These differences suggest unique functional characteristics for each subgroup in addition to their particular metal specificity.


P-type ATPase CPx-ATPase Cu-ATPase Metal binding site Zinc Cadmium Cobalt Copper Silver CopA CadA ZntA CopB 



I thank Kristin Wobbe and Atin Mandal for helpful discussions and critical review of the manuscript, and Win Cheung and Melinda Palma for their assistance with sequence download, file organization and listing. This work was supported by the National Institute of Health Grant R15 GM64419 and American Chemical Society—The Petroleum Research Fund Grant #36628-AC.


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© Springer-Verlag New York Inc. 2003

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryWorcester Polytechnic Institute, 100 Institute Rd., Worcester, MA 01609USA

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