Structural plasticity of the selectivity filter in a nonselective ion channel

Abstract

The sodium potassium ion channel (NaK) is a nonselective ion channel that conducts both sodium and potassium across the cellular membrane. A new crystallographic structure of NaK reveals conformational differences in the residues that make up the selectivity filter between the four subunits that form the ion channel and the inner helix of the ion channel. The crystallographic structure also identifies a side-entry, ion-conduction pathway for Na+ permeation that is unique to NaK. NMR studies and molecular dynamics simulations confirmed the dynamical nature of the top part of the selectivity filter and the inner helix in NaK as also observed in the crystal structure. Taken together, these results indicate that the structural plasticity of the selectivity filter combined with the dynamics of the inner helix of NaK are vital for the efficient conduction of different ions through the non-selective ion channel of NaK.

Ion-dependent structure, dynamics, and allosteric coupling in a non-selective cation channel

“…Interestingly, a putative Na + binding site behind the SF was proposed to stabilize the alternate conformation of D66 seen in the recently published 6V8Y structure of NaK. 31 The break in SF symmetry in TRPV1 is also is reminiscent of results for NaK, where Na + permeation only occurred in forced asymmetric states 13 , although Na + could permeate the TRPV1 SF in both symmetric and asymmetric conformations. 36 The appearance of multiple states for several SF residues in the presence of Na + could indicate a break in SF symmetry in our NMR samples and support the notion that Na + may permeate NaK in an asymmetric filter conformation.…”

“…Observed CSPs are in accord with two recent structures of NaK solubilized in DM -a microED structure solved in Na + (6CPV) 38 and a new X-ray structure solved in mixed ion conditions (6V8Y). 31 In both structures, N68 is seen to adopt alternative conformations that result in changes to backbone φ and ψ angles for N68 and F69, as well as slight reorientation of the F69 sidechain. Accordingly, we see large CSPs for N68 HN, Cα, and C' and F69 HN, Cα, and C' between Na + and K + (Fig.…”

“…The new X-ray structure also shows a reorientation of the carbonyl group for D66 in one protomer. 31 This reorientation largely affects the conformation of D66 C' and G67 HN.…”

“…13 A density assigned to a Na + ion was also resolved at this site in another recently published crystal structure. 31 The extent of backbone CSPs in the SF beyond these residues are difficult to explain solely based on changes in ion occupancy. Additionally, CSPs are observed for the methyl groups of V64, V59, L48, and I84, located behind the SF.…”

A novel ion conducting route besides the central pore in an inherited mutant of G-protein-gated inwardly rectifying K+ channel

“…2k and 3f). This novel ion permeation route is similar to a side entry pathway for Na + permeation through the sodium potassium (NaK) channel (31,32). The SF of the NaK channel is constructed by TVGDG, with D66 diverging from the conserved SF sequence of K + channels.…”