4.6 Article

The Voltage-Dependent Deactivation of the KvAP Channel Involves the Breakage of Its S4 Helix

期刊

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fmolb.2020.00162

关键词

Kv channel; resting state; molecular dynamics; voltage-sensor domain; pore domain; avidin accessibility

资金

  1. Swiss National Science Foundation [PP00P3_139205]
  2. Swiss National Supercomputing Centre (CSCS) [s421, s545, sm09, s968]
  3. Swiss National Science Foundation (SNF) [PP00P3_139205] Funding Source: Swiss National Science Foundation (SNF)

向作者/读者索取更多资源

Voltage-gated potassium channels (Kv) allow ion permeation upon changes of the membrane electrostatic potential (Vm). Each subunit of these tetrameric channels is composed of six transmembrane helices, of which the anti-parallel helix bundle S1-S4 constitutes the voltage-sensor domain (VSD) and S5-S6 forms the pore domain. Here, using 82 molecular dynamics (MD) simulations involving 266 replicated VSDs, we report novel responses of the archaebacterial potassium channel KvAP to membrane polarization. We show that the S4 alpha-helix, which is straight in the experimental crystal structure solved under depolarized conditions (Vm similar to 0), breaks into two segments when the cell membrane is hyperpolarized (Vm << 0), and reversibly forms a single straight helix following depolarization (Vm = 0). The outermost segment of S4 translates along the normal to the membrane, bringing new perspective to previously paradoxical accessibility experiments that were initially thought to imply the displacement of the whole VSD across the membrane. The novel model is applied through steered and unbiased MD simulations to the recently solved whole structure of KvAP. The simulations show that the resting state involves a re-orientation of the S5 alpha-helix by similar to 5-6 degrees in respect to the normal of the bilayer, which could result in the constriction and closure of the selectivity filter. Our findings support the idea that the breakage of S4 under (hyper)polarization is a general feature of Kv channels with a non-swapped topology.

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