Crystal structure of an inactivated mutant mammalian voltage-gated K+ channel (original) (raw)

2017, Nature Structural & Molecular Biology

C-type inactivation underlies important roles played by voltage-gated K + (Kv) channels. Functional studies have provided strong evidence that a common underlying cause of this type of inactivation is an alteration near the extracellular end of the channel's ion selectivity filter. Unlike N-type inactivation, which is known to reflect occlusion of the channel's intracellular end, the structural mechanism of C-type inactivation remains controversial and may have many detailed variations. Here, we report that in voltage-gated Shaker K + channels lacking N-type inactivation, a mutation enhancing inactivation disrupts the outermost K + site in the selectivity filter. Furthermore, in a crystal structure of the Kv1.2-2.1 chimeric channel bearing the same mutation, the outermost K + site, which is formed by eight carbonyl oxygen atoms, appears to be slightly too small to readily accommodate a K + ion and in fact exhibits little ion density; this structural finding is consistent with the functional hallmark characteristic of C-type inactivation. Kv channels underlie the repolarization phase of the action potential in excitable cells including nerve and heart cells. The channel activation gate is controlled by membrane voltage such that it opens upon membrane depolarization and closes on hyperpolarization 1, 2. However, even when depolarization is maintained and the activation gate remains open, most Kv channels still enter a nonconducting state, a process called inactivation. Two mechanistically distant types of inactivation are commonly recognized 3-5 : N-type inactivation, which results from occlusion of the channel's ion pore by the Nterminus of either the channel protein itself or its (auxiliary) β subunit 4-6 , and C-type inactivation, whose mechanistic interpretation presently remains controversial. C-type inactivation enables Kv channels to perform important tasks such as shaping cardiac action potentials to allow sufficient Ca 2+ influx to trigger effective myocyte contraction and