Permeation mechanisms through the selectivity filter and the open helix bundle crossing gate of GIRK2
| Autor: | Lei Wang, Liang Hu, Chin-Ling Chen, Dai-Lin Li |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
lcsh:Biotechnology
Biophysics Gating Molecular dynamics Biochemistry Ion 03 medical and health sciences 0302 clinical medicine Structural Biology lcsh:TP248.13-248.65 Genetics G protein-coupled inwardly-rectifying potassium channel G protein-gated inwardly rectifying K+ 2 (GIRK2) permeation mechanism 030304 developmental biology Helix bundle 0303 health sciences Chemistry Inward-rectifier potassium ion channel Permeation Helix bundle crossing gate Computer Science Applications 030220 oncology & carcinogenesis Inward rectifier potassium (Kir) channel Selectivity Biotechnology Research Article |
| Zdroj: | Computational and Structural Biotechnology Journal Computational and Structural Biotechnology Journal, Vol 18, Iss, Pp 3950-3958 (2020) |
| ISSN: | 2001-0370 |
| Popis: | Graphical abstract Permeation mechanisms through the selectivity filter (SF) and helix bundle crossing (HBC) gate of GIRK2 channel. Water and K+ ions co-translocate through the SF in a water-K+ coupled manner from the extracellular matrix into the intracellular side with the aid of an external electric field. A tilt of the SF affects its recognition efficiency. A 4-K+ occupancy in the SF-HBC cavity is required for the permeation through an open HBC; whilst the three K+ ions around E152 help to abolish the unfavorable cation-dipole interactions to overcome the energy barrier; the fourth K+ near HBC gets ready for the inward transport. G protein-gated inwardly rectifying potassium channels (GIRK) are essential for the regulation of cellular excitability, a physiological function that relies critically on the conduction of K+ ions, which is dependent on two molecular mechanisms, namely selectivity and gating. Molecular Dynamics (MD) studies have shown that K+ conduction remains inefficient even with open channel gates, therefore further detailed study on the permeation events is required. In this study, all-atom MD simulations were employed to investigate the permeation mechanism through the GIRK2 selectivity filter (SF) and its open helix bundle crossing (HBC) gate. Our results show that it is the SF rather than the HBC or the G-loop gate that determines the permeation efficiency upon activation of the channel. SF-permeation is accomplished by a water-K+ coupled mechanism and the entry to the S1 coordination site is likely affected by a SF tilt. Moreover, we show that a 4-K+ occupancy in the SF-HBC cavity is required for the permeation through an open HBC, where three K+ ions around E152 help to abolish the unfavorable cation-dipole interactions that function as an energy barrier, while the fourth K+ located near the HBC allows for the inward transport. These findings facilitate further understanding of the dynamic permeation mechanisms through GIRK2 and potentially provide an alternative regulatory approach for the Kir3 family given the overall high evolutionary residue conservation. |
| Databáze: | OpenAIRE |
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