Domain Reorientation and Rotation of an Intracellular Assembly Regulate Conduction in Kir Potassium Channels

Abstract

Potassium channels embedded in cell membranes employ gates to regulate K+ current. While a specific constriction in the permeation pathway has historically been implicated in gating, recent reports suggest that the signature ion selectivity filter located in the outer membrane leaflet may be equally important. Inwardly rectifying K+ channels also control the directionality of flow, using intracellular polyamines to stem ion efflux by a valve-like action. This study presents crystallographic evidence of interdependent gates in the conduction pathway and reveals the mechanism of polyamine block. Reorientation of the intracellular domains, concomitant with activation, instigates polyamine release from intracellular binding sites to block the permeation pathway. Conformational adjustments of the slide helices, achieved by rotation of the cytoplasmic assembly relative to the pore, are directly correlated to the ion configuration in the selectivity filter. Ion redistribution occurs irrespective of the constriction, suggesting a more expansive role of the selectivity filter in gating than previously appreciated.

Decomposition of Slide Helix Contributions to ATP-dependent Inhibition of Kir6.2 Channels

“…Our findings indicate that this interface depends significantly on Asp-58, a residue we refer to as the "aspartate anchor." A model to explain our findings is that when the Asp-58 TMD-CTD anchor is in place, gating kinetics are slow, possibly because conformational changes of the TMD and CTD are coupled (16,17,49), resulting in an energetic barrier to opening. Mutations in the vicinity of the ATP binding site (i.e.…”

A Pore Residue of the KCNQ3 Potassium M-Channel Subunit Controls Surface Expression

“…A recent report presents crystallographic evidence for structural connections between the inner vestibule and cytosolic domains of KirBac3.1 potassium channels (Clarke et al, 2010). The transport machinery might recognize structural rearrangements in cytosolic domains of KCNQ3 channels transmitted from the inner vestibule by mechanisms analogous to those described for KirBac3.1.…”

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

“…Gating at the selectivity filter is commonly referred to as C-type inactivation. Although a conformational rearrangement of the selectivity filter (10) underlies the final step of inactivation gating, there is increasing evidence, from a variety of potassium channels (11)(12)(13), that more widespread rearrangements of the channel protein precede this final nonconducting conformation.…”