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Structural Basis for Heavy Metal Detoxification by an Atm1-Type ABC Exporter

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Science  07 Mar 2014:
Vol. 343, Issue 6175, pp. 1133-1136
DOI: 10.1126/science.1246489

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Abstract

Although substantial progress has been achieved in the structural analysis of exporters from the superfamily of adenosine triphosphate (ATP)–binding cassette (ABC) transporters, much less is known about how they selectively recognize substrates and how substrate binding is coupled to ATP hydrolysis. We have addressed these questions through crystallographic analysis of the Atm1/ABCB7/HMT1/ABCB6 ortholog from Novosphingobium aromaticivorans DSM 12444, NaAtm1, at 2.4 angstrom resolution. Consistent with a physiological role in cellular detoxification processes, functional studies showed that glutathione derivatives can serve as substrates for NaAtm1 and that its overexpression in Escherichia coli confers protection against silver and mercury toxicity. The glutathione binding site highlights the articulated design of ABC exporters, with ligands and nucleotides spanning structurally conserved elements to create adaptable interfaces accommodating conformational rearrangements during the transport cycle.

Crossing the Membrane

Adenosine triphosphate (ATP)–binding cassette (ABC) transporters couple ATP hydrolysis to the translocation of a wide variety of substrates across cell membranes. Srinivasan et al. (p. 1137) describe the structure of a yeast mitochondrial transporter involved in Fe-S protein biogenesis. The structure reveals bound glutathione, which suggests that glutathione is part of the translocated substrate. J. Y. Lee et al. (p. 1133) describe the structure of a bacterial ABC transporter that confers protection against silver and mercury. This protein also binds glutathione derivatives. The structure provides insight into how ligand interactions are coupled to ATP hydrolysis.

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