Determinants of cation transport selectivity: Equilibrium binding and transport kinetics

Abstract

The crystal structures of channels and transporters reveal the chemical nature of ion-binding sites and, thereby, constrain mechanistic models for their transport processes. However, these structures, in and of themselves, do not reveal equilibrium selectivity or transport preferences, which can be discerned only from various functional assays. In this Review, I explore the relationship between cation transport protein structures, equilibrium binding measurements, and ion transport selectivity. The primary focus is on K(+)-selective channels and nonselective cation channels because they have been extensively studied both functionally and structurally, but the principles discussed are relevant to other transport proteins and molecules.

Figure 1.

Structure of a generic tetrameric cation channel. The pore domain (in blue) is found in all tetrameric cation channels. This region of the channel selectively transports ions across the membrane and integrates regulatory signals through transmembrane and intracellular regulatory domains that can be attached to the N or C terminus of the channel (in gray). In the K⁺ channel pore shown here, the selectivity filter (in yellow) is composed of discrete ion-binding sites indicated with the green spheres. Other tetrameric cation channels (Na⁺, Ca²⁺, and nonselective) have the same overall architecture but with a different selectivity filter.

Figure 2.

Comparison of ion distribution in MthK K⁺ channel. (Left) The selectivity filter of MthK with K⁺ ions (Protein Data Bank [PDB] accession no. 3LDC). An F_o–F_c ion omit map (4σ) shows the electron density in the filter. (Right) The selectivity filter of MthK with Na⁺ ions (PDB accession no. 3LDE). An F_o–F_c ion omit map (4σ) shows the electron density in the filter. Structures are from Ye et al. (2010).

Figure 3.

The selectivity filter of the nonselective NaK and NaK2CNG-D channels. An F_o–F_c ion omit map (5σ) shows the electron density in the filter. (A) The WT NaK channel in the presence of K⁺ ions (PDB accession no. 3E8H). (B) Comparison of electron density in nonselective NaK2CNG-D channel. (Left) The selectivity filter of NaK2CNG-D with bound K⁺ ions (PDB accession no. 3K03). (Right) The selectivity filter of NaK2CNG-D with bound Na⁺ ions (PDB accession no. 3K04). Structures are from Alam and Jiang (2009b) and Derebe et al. (2011a).

Figure 4.

Crystal structures of K⁺-selective [2,2,2]cryptand. (Left) K⁺ ion is green with an average O–K⁺ distance of 2.8 Å. (Middle) Na⁺ ion is orange with an average O–Na⁺ distance of 2.6 Å. (Right) Li⁺ ion is yellow with an average O–Na⁺ distance of 2.4 Å. Structures are from Chekhlov (2003, 2005a,b).