تقرير
Lipid-mediated hydrophobic gating in the BK potassium channel
| العنوان: | Lipid-mediated hydrophobic gating in the BK potassium channel |
|---|---|
| المؤلفون: | Coronel, Lucia, Di Muccio, Giovanni, Rothberg, Brad, Giacomello, Alberto, Carnevale, Vincenzo |
| سنة النشر: | 2024 |
| المجموعة: | Physics (Other) Quantitative Biology |
| مصطلحات موضوعية: | Quantitative Biology - Biomolecules, Physics - Biological Physics, Physics - Chemical Physics |
| الوصف: | The large-conductance, calcium-activated potassium (BK) channel lacks the typical intracellular bundle-crossing gate present in most ion channels of the 6TM family. This observation, initially inferred from Ca$^{2+}$-free-pore accessibility experiments and recently corroborated by a CryoEM structure of the non-conductive state, raises a puzzling question: how can gating occur in absence of steric hindrance? To answer this question, we carried out molecular simulations and accurate free energy calculations to obtain a microscopic picture of the sequence of events that, starting from a Ca$^{2+}$-free state leads to ion conduction upon Ca$^{2+}$ binding. Our results highlight an unexpected role for annular lipids, which turn out to be an integral part of the gating machinery. Due to the presence of fenestrations, the "closed" Ca$^{2+}$-free pore can be occupied by the methyl groups from the lipid alkyl chains. This dynamic occupancy triggers and stabilizes the nucleation of a vapor bubble into the inner pore cavity, thus hindering ion conduction. By contrast, Ca$^{2+}$ binding results into a displacement of these lipids outside the inner cavity, lowering the hydrophobicity of this region and thus allowing for pore hydration and conduction. This lipid-mediated hydrophobic gating rationalizes several seemingly problematic experimental observations, including the state-dependent pore accessibility of blockers. |
| نوع الوثيقة: | Working Paper |
| URL الوصول: | http://arxiv.org/abs/2405.04644 |
| رقم الأكسشن: | edsarx.2405.04644 |
| قاعدة البيانات: | arXiv |
| الوصف غير متاح. |