On the activation—inactivation coupling in Shaker potassium channels

Abstract

The "ball-and-chain' model suggests the e~istence of a tlegativc site which may attract the positively charged inactivation bali to occlude the pore when the channel is in the open state. For Shah'er K + channels, we propose that the state-dependent negative site be tryptophan435, which becomes negatively charged after receiving an electron from tyrosine.445. The kinetic scheme for the channel's activation-inactivation coupling as derived from the YW.g:tted model resembles a successful 'scheme 8' proposed by Zagotta and Aldrich. Oar model suggests that the final rapid voltageindependent transition to the open state is due to the deprotonation of tyrosine-445.

Intrinsically disordered protein

“…The PEVK region is very likely to be structurally disordered and may function as a rubber-like entropic spring that helps to restore over-stretched muscle cells to their natural, relaxed length. 225 K 226,227,228 The timing of this closure is critical to proper nerve cell function and evidently depends on the length and flexibility of the chain. Here we suggest that this flexiblity be recognized as an entropic clock due to its important function as a timing device.…”

Ligand‐activated ion channels may share common gating mechanisms with the Shaker potassium channel

“…After electron transfer, the acceptor becomes negatively charged, but the donor will quickly deprotonate to become a radical [4]. This feature has been able to explain successfully the Bating mechanism of Shaker K' channels [5]. In this model, the physical gate is located at tyrosine-445 (Y445) and tryptophan-(W435).…”

“…If this is the case, the gating mechanisms for cNG and S/&cer K' channels are essentially the same. The agonist of the cNG channel is equivalent to D447 for stimulating electron transfer, and the tyrosine at the agonist binding site is similar to Y445 as the electron donor [4,5]. The major difference is that the tyrosine at the agonist binding site, being away from the pore, is no longer the selectivity filter.…”

“…In contrast, the positively charged agonist would induce electron transfer from the pore to the agonist binding site. In the YW electron transfer system, the electron acceptor becomes negatively charged, but the electron donor will quickly deprotonate to become a radical [4,5]. Therefore, the channel's opening for 'positive agonist' channels cannot be controlled by the electrostatic repulsion even if their M2 comained tryptophan or tyrosine.…”

“…It is interesting to note, from the above sequence alignment, that Y445 and D447 are absent from the cNG channel. In the YWgated model, D447 could be the major voltage sensor [4,5]. The absence of Y445 and D447 may explain why the cNG channel is not K+-selective and not voltagesensitive [ 1,2].…”