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Pore size matters for potassium channel conductance

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ABSTRACT

Ion channels are membrane proteins that mediate efficient ion transport across the hydrophobic core of cell membranes, an unlikely process in their absence. K+ channels discriminate K+ over cations with similar radii with extraordinary selectivity and display a wide diversity of ion transport rates, covering differences of two orders of magnitude in unitary conductance. The pore domains of large- and small-conductance K+ channels share a general architectural design comprising a conserved narrow selectivity filter, which forms intimate interactions with permeant ions, flanked by two wider vestibules toward the internal and external openings. In large-conductance K+ channels, the inner vestibule is wide, whereas in small-conductance channels it is narrow. Here we raise the idea that the physical dimensions of the hydrophobic internal vestibule limit ion transport in K+ channels, accounting for their diversity in unitary conductance.

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Structural features of the KcsA channel and K+ coordination structure in the pore. (A and B) Membrane-omitted side and top views of the KcsA K+ channel (PDB ID 1K4C). Each monomer is a two–transmembrane segment peptide position around the pore at the axis of fourfold symmetry forming the K+ selective pore (green spheres). (C) High-resolution electronic density map showing the two diagonal subunits and the orientation of the carbonyl oxygen atoms to coordinate K+ ions. The numbers correspond to the four binding sites determined by the sequence TVGYG. (D) Antiprism and cubic cages forming the selectivity filter binding sites, the distances d1–d5 and heights h1–h4 correspond to the inter-oxygen separations described in Table 1 for several K+ channel structures. A and B were inspired by Doyle et al. (1998), C was modified from Zhou et al. (2001) with permission from Macmillan Publishers Ltd., and D was inspired by Chen et al. (2014).
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fig1: Structural features of the KcsA channel and K+ coordination structure in the pore. (A and B) Membrane-omitted side and top views of the KcsA K+ channel (PDB ID 1K4C). Each monomer is a two–transmembrane segment peptide position around the pore at the axis of fourfold symmetry forming the K+ selective pore (green spheres). (C) High-resolution electronic density map showing the two diagonal subunits and the orientation of the carbonyl oxygen atoms to coordinate K+ ions. The numbers correspond to the four binding sites determined by the sequence TVGYG. (D) Antiprism and cubic cages forming the selectivity filter binding sites, the distances d1–d5 and heights h1–h4 correspond to the inter-oxygen separations described in Table 1 for several K+ channel structures. A and B were inspired by Doyle et al. (1998), C was modified from Zhou et al. (2001) with permission from Macmillan Publishers Ltd., and D was inspired by Chen et al. (2014).

Mentions: The crystallographic structure of the KcsA bacterial K+ channel resolved at 3.2 Å by Doyle et al. (1998) revealed for the first time how the pore of a K+ channel looks (Fig. 1, A and B). The protein has a tetrameric organization around the pore placed in its axis of symmetry. Although the structure corresponded to that of a closed channel, it showed several, previously anticipated, functional features: (a) The pore hosts several K+ ions in single-file order as Hodgkin and Keynes predicted 60 years ago (Hodgkin and Keynes, 1955). (b) The pore has a narrow selectivity filter located toward the external entrance and is flanked internally by a wider internal vestibule as anticipated by Armstrong and Bezanilla (Armstrong, 1971; Bezanilla and Armstrong, 1972; Miller, 1982; Latorre and Miller, 1983). (c) K+ ions are partially hydrated in the narrow section of the pore, as Mullins, Bezanilla, and Armstrong proposed half a century ago (Mullins, 1959; Armstrong, 1971; Bezanilla and Armstrong, 1972; Hille, 1973). Although the structural analysis could not resolve interatomic bond orientation, it was hypothesized that carbonyl oxygens from the signature sequence in the peptide backbone, TVGYG, shape the anticipated low-field-strength K+ binding sites by forming surrogate hydration cages in the filter (Eisenman, 1962; Heginbotham et al., 1994). The presence of these expected features in a single crystallographic structure gave this study immediate acceptance.


Pore size matters for potassium channel conductance
Structural features of the KcsA channel and K+ coordination structure in the pore. (A and B) Membrane-omitted side and top views of the KcsA K+ channel (PDB ID 1K4C). Each monomer is a two–transmembrane segment peptide position around the pore at the axis of fourfold symmetry forming the K+ selective pore (green spheres). (C) High-resolution electronic density map showing the two diagonal subunits and the orientation of the carbonyl oxygen atoms to coordinate K+ ions. The numbers correspond to the four binding sites determined by the sequence TVGYG. (D) Antiprism and cubic cages forming the selectivity filter binding sites, the distances d1–d5 and heights h1–h4 correspond to the inter-oxygen separations described in Table 1 for several K+ channel structures. A and B were inspired by Doyle et al. (1998), C was modified from Zhou et al. (2001) with permission from Macmillan Publishers Ltd., and D was inspired by Chen et al. (2014).
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5037345&req=5

fig1: Structural features of the KcsA channel and K+ coordination structure in the pore. (A and B) Membrane-omitted side and top views of the KcsA K+ channel (PDB ID 1K4C). Each monomer is a two–transmembrane segment peptide position around the pore at the axis of fourfold symmetry forming the K+ selective pore (green spheres). (C) High-resolution electronic density map showing the two diagonal subunits and the orientation of the carbonyl oxygen atoms to coordinate K+ ions. The numbers correspond to the four binding sites determined by the sequence TVGYG. (D) Antiprism and cubic cages forming the selectivity filter binding sites, the distances d1–d5 and heights h1–h4 correspond to the inter-oxygen separations described in Table 1 for several K+ channel structures. A and B were inspired by Doyle et al. (1998), C was modified from Zhou et al. (2001) with permission from Macmillan Publishers Ltd., and D was inspired by Chen et al. (2014).
Mentions: The crystallographic structure of the KcsA bacterial K+ channel resolved at 3.2 Å by Doyle et al. (1998) revealed for the first time how the pore of a K+ channel looks (Fig. 1, A and B). The protein has a tetrameric organization around the pore placed in its axis of symmetry. Although the structure corresponded to that of a closed channel, it showed several, previously anticipated, functional features: (a) The pore hosts several K+ ions in single-file order as Hodgkin and Keynes predicted 60 years ago (Hodgkin and Keynes, 1955). (b) The pore has a narrow selectivity filter located toward the external entrance and is flanked internally by a wider internal vestibule as anticipated by Armstrong and Bezanilla (Armstrong, 1971; Bezanilla and Armstrong, 1972; Miller, 1982; Latorre and Miller, 1983). (c) K+ ions are partially hydrated in the narrow section of the pore, as Mullins, Bezanilla, and Armstrong proposed half a century ago (Mullins, 1959; Armstrong, 1971; Bezanilla and Armstrong, 1972; Hille, 1973). Although the structural analysis could not resolve interatomic bond orientation, it was hypothesized that carbonyl oxygens from the signature sequence in the peptide backbone, TVGYG, shape the anticipated low-field-strength K+ binding sites by forming surrogate hydration cages in the filter (Eisenman, 1962; Heginbotham et al., 1994). The presence of these expected features in a single crystallographic structure gave this study immediate acceptance.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Ion channels are membrane proteins that mediate efficient ion transport across the hydrophobic core of cell membranes, an unlikely process in their absence. K+ channels discriminate K+ over cations with similar radii with extraordinary selectivity and display a wide diversity of ion transport rates, covering differences of two orders of magnitude in unitary conductance. The pore domains of large- and small-conductance K+ channels share a general architectural design comprising a conserved narrow selectivity filter, which forms intimate interactions with permeant ions, flanked by two wider vestibules toward the internal and external openings. In large-conductance K+ channels, the inner vestibule is wide, whereas in small-conductance channels it is narrow. Here we raise the idea that the physical dimensions of the hydrophobic internal vestibule limit ion transport in K+ channels, accounting for their diversity in unitary conductance.

No MeSH data available.


Related in: MedlinePlus