K2P channel C-type gating involves asymmetric selectivity filter order-disorder transitions
| Autor: | Andrew M. Natale, Daniel L. Minor, Michael Grabe, Armin Wagner, Sara Capponi, Fayal Abderemane-Ali, David Crottès, Ramona Duman, John M. Rosenberg, Marco Lolicato |
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| Rok vydání: | 2020 |
| Předmět: |
Potassium
Biophysics chemistry.chemical_element Gating Biochemistry 03 medical and health sciences Molecular dynamics 0302 clinical medicine Ion binding Structural Biology Research Articles 030304 developmental biology K2p channel 0303 health sciences Multidisciplinary Anomalous scattering Chemistry Hydrogen bond Neurosciences SciAdv r-articles Biological Sciences Potassium channel Electrophysiology Transmembrane domain Physical Sciences Chemical Sciences Selectivity 030217 neurology & neurosurgery Research Article |
| Zdroj: | Science advances, vol 6, iss 44 Science Advances BIOPHYSICAL JOURNAL, vol 120, iss 3 |
| Popis: | The innately heterodimeric K2P filter permits two C-type gating mechanisms, pinching and dilation, to operate in one channel. K2P potassium channels regulate cellular excitability using their selectivity filter (C-type) gate. C-type gating mechanisms, best characterized in homotetrameric potassium channels, remain controversial and are attributed to selectivity filter pinching, dilation, or subtle structural changes. The extent to which such mechanisms control C-type gating of innately heterodimeric K2Ps is unknown. Here, combining K2P2.1 (TREK-1) x-ray crystallography in different potassium concentrations, potassium anomalous scattering, molecular dynamics, and electrophysiology, we uncover unprecedented, asymmetric, potassium-dependent conformational changes that underlie K2P C-type gating. These asymmetric order-disorder transitions, enabled by the K2P heterodimeric architecture, encompass pinching and dilation, disrupt the S1 and S2 ion binding sites, require the uniquely long K2P SF2-M4 loop and conserved “M3 glutamate network,” and are suppressed by the K2P C-type gate activator ML335. These findings demonstrate that two distinct C-type gating mechanisms can operate in one channel and underscore the SF2-M4 loop as a target for K2P channel modulator development. |
| Databáze: | OpenAIRE |
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