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Asymmetric Switching in a Homodimeric ABC Transporter: A Simulation Study

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  • Jussi Aittoniemi
  • Heidi de Wet
  • Frances M Ashcroft
  • Mark S P Sansom

Abstract

ABC transporters are a large family of membrane proteins involved in a variety of cellular processes, including multidrug and tumor resistance and ion channel regulation. Advances in the structural and functional understanding of ABC transporters have revealed that hydrolysis at the two canonical nucleotide-binding sites (NBSs) is co-operative and non-simultaneous. A conserved core architecture of bacterial and eukaryotic ABC exporters has been established, as exemplified by the crystal structure of the homodimeric multidrug exporter Sav1866. Currently, it is unclear how sequential ATP hydrolysis arises in a symmetric homodimeric transporter, since it implies at least transient asymmetry at the NBSs. We show by molecular dynamics simulation that the initially symmetric structure of Sav1866 readily undergoes asymmetric transitions at its NBSs in a pre-hydrolytic nucleotide configuration. MgATP-binding residues and a network of charged residues at the dimer interface are shown to form a sequence of putative molecular switches that allow ATP hydrolysis only at one NBS. We extend our findings to eukaryotic ABC exporters which often consist of two non-identical half-transporters, frequently with degeneracy substitutions at one of their two NBSs. Interestingly, many residues involved in asymmetric conformational switching in Sav1866 are substituted in degenerate eukaryotic NBS. This finding strengthens recent suggestions that the interplay of a consensus and a degenerate NBS in eukaroytic ABC proteins pre-determines the sequence of hydrolysis at the two NBSs.Author Summary: ABC transporters are a large family of membrane proteins present in all organisms. Typically, they utilize ATP hydrolysis, the most prominent biological energy source, to translocate substrates into cells (e.g., bacterial nutritient uptake) or out of cells (e.g., multidrug exporters that contribute to antimicrobial resistance in bacteria and resistance to chemotherapeutic drugs in cancer). Also clinically relevant non-transport roles have been identified among ABC proteins. ABC transporters bind two molecules of ATP but do not hydrolyze them simultaneously. Therefore, an ABC transporter that consists of two symmetric halves must temporarily adopt asymmetric conformations at the two ATP-binding sites. Such transient conformational changes are difficult to address biochemically, but may be amenable to study by simulation methods, leading to future experiments. We employ molecular dynamics simulations to study how asymmetric switching might occur in the homodimeric bacterial ABC multidrug exporter Sav1866. The simulations suggest a mechanism of conformational switching that encompasses the ATP-binding sites and their interface towards the substrate-binding site. We extend our findings to show how asymmetric residue substitutions may render the switching process non-stochastic in mammalian Sav1866-like ABC exporters. This contributes to ongoing discussions about the role of two dissimilar ATP-binding sites in clinically relevant ABC proteins.

Suggested Citation

  • Jussi Aittoniemi & Heidi de Wet & Frances M Ashcroft & Mark S P Sansom, 2010. "Asymmetric Switching in a Homodimeric ABC Transporter: A Simulation Study," PLOS Computational Biology, Public Library of Science, vol. 6(4), pages 1-10, April.
  • Handle: RePEc:plo:pcbi00:1000762
    DOI: 10.1371/journal.pcbi.1000762
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    References listed on IDEAS

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    1. Roger J. P. Dawson & Kaspar P. Locher, 2006. "Structure of a bacterial multidrug ABC transporter," Nature, Nature, vol. 443(7108), pages 180-185, September.
    2. David C. Gadsby & Paola Vergani & László Csanády, 2006. "The ABC protein turned chloride channel whose failure causes cystic fibrosis," Nature, Nature, vol. 440(7083), pages 477-483, March.
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    1. Heidi Koldsø & Pernille Noer & Julie Grouleff & Henriette Elisabeth Autzen & Steffen Sinning & Birgit Schiøtt, 2011. "Unbiased Simulations Reveal the Inward-Facing Conformation of the Human Serotonin Transporter and Na+ Ion Release," PLOS Computational Biology, Public Library of Science, vol. 7(10), pages 1-14, October.

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