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Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport.

Varma S, Rogers DM, Pratt LR, Rempe SB - J. Gen. Physiol. (2011)

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, USA.

ABSTRACT

The advent of atomic resolution structures of ion-selective channels made possible the transition from black box models to molecular descriptions for considering the design principles underlying selectivity in a flexible selectivity filter. Simple theoretical models applied to interpret the complex behaviors observed in whole molecule experiments and molecular simulations led to suggestions that ligand type is of primary importance in determining selectivity. As discussed in this Perspective, this view is incomplete. Models that focus on chemical forces as a primary design principle do not explain why carbonyl ligands produce K+ selectivity in eightfold K+ channel–binding sites, but yield Na+ selectivity in liquid analogues (Fig. 2). Additionally, these models have not explained why chemically identical binding sites in the strongly selective KcsA channel show significantly different selectivities in simulations of whole channels. The same question applies to NaK channels, which lack selectivity despite sharing two chemically identical binding sites with strongly selective K+ channels. We are left with the conclusion that ion selectivity requires consideration of both ligand characteristics and the forces influencing binding site composition and structure.

Recent simulations support the view that interactions with the more distant environment of the membrane transport molecule can modify properties of the binding site and influence selective binding. In the case of K+ channels, restricted carbonyl motion or a decrease in their availability to the protein environment can drive up ion coordination numbers in the selectivity filter, leading to K+ selectivity. A snug fit as in valinomycin can be enforced by an environment that stabilizes intra-molecular hydrogen bonding, achieving selectivity without over-coordination through a constraint on cavity size. The importance of environmental controls on binding sites has since been recognized in several recent works (see, for example, Fowler et al., 2008; Miloshevsky and Jordan, 2008; Vora et al., 2008; Dixit et al., 2009; Dudev and Lim, 2009; Yu and Roux, 2009; Yu et al., 2009, 2010b; Roux, 2010; Rogers and Rempe, 2011). This Perspective provides a foundation necessary for understanding the more complex behavior of selective ion transport through membranes.

This Perspectives series includes articles by Andersen, Alam and Jiang, Nimigean and Allen, Roux et al., and Dixit and Asthagiri.

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Representative binding modes of Na+ and K+ ions in structural motifs of K+-selective membrane transport molecules. (Note that only two units from the tetrameric selectivity filters are shown for clarity.) (A) The selectivity filter of KcsA (Zhou et al., 2001) adopts different configurations under conditions of high and (B) low K+ concentrations, presenting K+ with different sets of binding modes. (C) Under rare conditions when Na+ binds to the KcsA filter, Na+ prefers a binding site different from K+ (Nimigean and Miller, 2002; Shrivastava et al., 2002; Lockless et al., 2007; Thompson et al., 2009). (D) The bacterial NaK channel, which belongs to the family of CNG channels, has a selectivity filter architecture similar to KcsA, but is only weakly selective for K+. Initially, low temperature x-ray data suggested binding modes for K+ that are identical to Na+. (E) Newer higher resolution crystallographic studies show more variety in Na+ binding, attributing electron density at the S3 site to competitive binding of a contaminant (orange) with Na+, with other Na+-binding sites between planes of carbonyl or hydroxyl oxygens (Alam and Jiang, 2009). (F) In comparison to KcsA and the NaK channel, the K+-selective bacterial toxin molecule (Dobler, 1981), valinomycin, binds K+ differently, using six (or fewer) carbonyl oxygens, instead of eight (or fewer) as in KcsA and NaK.
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fig1: Representative binding modes of Na+ and K+ ions in structural motifs of K+-selective membrane transport molecules. (Note that only two units from the tetrameric selectivity filters are shown for clarity.) (A) The selectivity filter of KcsA (Zhou et al., 2001) adopts different configurations under conditions of high and (B) low K+ concentrations, presenting K+ with different sets of binding modes. (C) Under rare conditions when Na+ binds to the KcsA filter, Na+ prefers a binding site different from K+ (Nimigean and Miller, 2002; Shrivastava et al., 2002; Lockless et al., 2007; Thompson et al., 2009). (D) The bacterial NaK channel, which belongs to the family of CNG channels, has a selectivity filter architecture similar to KcsA, but is only weakly selective for K+. Initially, low temperature x-ray data suggested binding modes for K+ that are identical to Na+. (E) Newer higher resolution crystallographic studies show more variety in Na+ binding, attributing electron density at the S3 site to competitive binding of a contaminant (orange) with Na+, with other Na+-binding sites between planes of carbonyl or hydroxyl oxygens (Alam and Jiang, 2009). (F) In comparison to KcsA and the NaK channel, the K+-selective bacterial toxin molecule (Dobler, 1981), valinomycin, binds K+ differently, using six (or fewer) carbonyl oxygens, instead of eight (or fewer) as in KcsA and NaK.

Mentions: Complications for explaining selectivity arise because the family of K+ channels exhibits a range of selectivities, from weakly selective HCN pacemaker K+ channels to strongly selective “maxi”-type K+ channels or their bacterial homologue, KcsA. Fig. 1 A illustrates the structure of a representative K+ channel (Zhou et al., 2001), the family of proteins primarily responsible for passive K+-selective transport. The narrowest region of the pore, referred to as the selectivity filter, is understood to impart K+ selectivity, although other portions of the channel also play a role. Diverse K+ channels typically share this filter architecture (Hille, 2001) according to sequence alignment (Shealy et al., 2003), x-ray structures of a variety of K+ channels, and a vast amount of physiological data. In light of this structural similarity, how does the variability in selectivity come about?


Perspectives on: ion selectivity: design principles for K+ selectivity in membrane transport.

Varma S, Rogers DM, Pratt LR, Rempe SB - J. Gen. Physiol. (2011)

Representative binding modes of Na+ and K+ ions in structural motifs of K+-selective membrane transport molecules. (Note that only two units from the tetrameric selectivity filters are shown for clarity.) (A) The selectivity filter of KcsA (Zhou et al., 2001) adopts different configurations under conditions of high and (B) low K+ concentrations, presenting K+ with different sets of binding modes. (C) Under rare conditions when Na+ binds to the KcsA filter, Na+ prefers a binding site different from K+ (Nimigean and Miller, 2002; Shrivastava et al., 2002; Lockless et al., 2007; Thompson et al., 2009). (D) The bacterial NaK channel, which belongs to the family of CNG channels, has a selectivity filter architecture similar to KcsA, but is only weakly selective for K+. Initially, low temperature x-ray data suggested binding modes for K+ that are identical to Na+. (E) Newer higher resolution crystallographic studies show more variety in Na+ binding, attributing electron density at the S3 site to competitive binding of a contaminant (orange) with Na+, with other Na+-binding sites between planes of carbonyl or hydroxyl oxygens (Alam and Jiang, 2009). (F) In comparison to KcsA and the NaK channel, the K+-selective bacterial toxin molecule (Dobler, 1981), valinomycin, binds K+ differently, using six (or fewer) carbonyl oxygens, instead of eight (or fewer) as in KcsA and NaK.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
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fig1: Representative binding modes of Na+ and K+ ions in structural motifs of K+-selective membrane transport molecules. (Note that only two units from the tetrameric selectivity filters are shown for clarity.) (A) The selectivity filter of KcsA (Zhou et al., 2001) adopts different configurations under conditions of high and (B) low K+ concentrations, presenting K+ with different sets of binding modes. (C) Under rare conditions when Na+ binds to the KcsA filter, Na+ prefers a binding site different from K+ (Nimigean and Miller, 2002; Shrivastava et al., 2002; Lockless et al., 2007; Thompson et al., 2009). (D) The bacterial NaK channel, which belongs to the family of CNG channels, has a selectivity filter architecture similar to KcsA, but is only weakly selective for K+. Initially, low temperature x-ray data suggested binding modes for K+ that are identical to Na+. (E) Newer higher resolution crystallographic studies show more variety in Na+ binding, attributing electron density at the S3 site to competitive binding of a contaminant (orange) with Na+, with other Na+-binding sites between planes of carbonyl or hydroxyl oxygens (Alam and Jiang, 2009). (F) In comparison to KcsA and the NaK channel, the K+-selective bacterial toxin molecule (Dobler, 1981), valinomycin, binds K+ differently, using six (or fewer) carbonyl oxygens, instead of eight (or fewer) as in KcsA and NaK.
Mentions: Complications for explaining selectivity arise because the family of K+ channels exhibits a range of selectivities, from weakly selective HCN pacemaker K+ channels to strongly selective “maxi”-type K+ channels or their bacterial homologue, KcsA. Fig. 1 A illustrates the structure of a representative K+ channel (Zhou et al., 2001), the family of proteins primarily responsible for passive K+-selective transport. The narrowest region of the pore, referred to as the selectivity filter, is understood to impart K+ selectivity, although other portions of the channel also play a role. Diverse K+ channels typically share this filter architecture (Hille, 2001) according to sequence alignment (Shealy et al., 2003), x-ray structures of a variety of K+ channels, and a vast amount of physiological data. In light of this structural similarity, how does the variability in selectivity come about?

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biological, Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, USA.

ABSTRACT

The advent of atomic resolution structures of ion-selective channels made possible the transition from black box models to molecular descriptions for considering the design principles underlying selectivity in a flexible selectivity filter. Simple theoretical models applied to interpret the complex behaviors observed in whole molecule experiments and molecular simulations led to suggestions that ligand type is of primary importance in determining selectivity. As discussed in this Perspective, this view is incomplete. Models that focus on chemical forces as a primary design principle do not explain why carbonyl ligands produce K+ selectivity in eightfold K+ channel–binding sites, but yield Na+ selectivity in liquid analogues (Fig. 2). Additionally, these models have not explained why chemically identical binding sites in the strongly selective KcsA channel show significantly different selectivities in simulations of whole channels. The same question applies to NaK channels, which lack selectivity despite sharing two chemically identical binding sites with strongly selective K+ channels. We are left with the conclusion that ion selectivity requires consideration of both ligand characteristics and the forces influencing binding site composition and structure.

Recent simulations support the view that interactions with the more distant environment of the membrane transport molecule can modify properties of the binding site and influence selective binding. In the case of K+ channels, restricted carbonyl motion or a decrease in their availability to the protein environment can drive up ion coordination numbers in the selectivity filter, leading to K+ selectivity. A snug fit as in valinomycin can be enforced by an environment that stabilizes intra-molecular hydrogen bonding, achieving selectivity without over-coordination through a constraint on cavity size. The importance of environmental controls on binding sites has since been recognized in several recent works (see, for example, Fowler et al., 2008; Miloshevsky and Jordan, 2008; Vora et al., 2008; Dixit et al., 2009; Dudev and Lim, 2009; Yu and Roux, 2009; Yu et al., 2009, 2010b; Roux, 2010; Rogers and Rempe, 2011). This Perspective provides a foundation necessary for understanding the more complex behavior of selective ion transport through membranes.

This Perspectives series includes articles by Andersen, Alam and Jiang, Nimigean and Allen, Roux et al., and Dixit and Asthagiri.

Show MeSH
Related in: MedlinePlus