Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel.
The mechanosensitive two-pore domain (K2P) K(+) channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Cell Press
2017
|
| _version_ | 1826288170532077568 |
|---|---|
| author | Aryal, P Jarerattanachat, V Clausen, M Schewe, M McClenaghan, C Argent, L Conrad, L Dong, Y Pike, A Carpenter, E Baukrowitz, T Sansom, M Tucker, S |
| author_facet | Aryal, P Jarerattanachat, V Clausen, M Schewe, M McClenaghan, C Argent, L Conrad, L Dong, Y Pike, A Carpenter, E Baukrowitz, T Sansom, M Tucker, S |
| author_sort | Aryal, P |
| collection | OXFORD |
| description | The mechanosensitive two-pore domain (K2P) K(+) channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the "down" to "up" conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer. |
| first_indexed | 2024-03-07T02:09:40Z |
| format | Journal article |
| id | oxford-uuid:a02f3096-8f94-4642-89ac-0a4a4aa1675f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:09:40Z |
| publishDate | 2017 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:a02f3096-8f94-4642-89ac-0a4a4aa1675f2022-03-27T02:03:43ZBilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a02f3096-8f94-4642-89ac-0a4a4aa1675fEnglishSymplectic Elements at OxfordCell Press2017Aryal, PJarerattanachat, VClausen, MSchewe, MMcClenaghan, CArgent, LConrad, LDong, YPike, ACarpenter, EBaukrowitz, TSansom, MTucker, SThe mechanosensitive two-pore domain (K2P) K(+) channels (TREK-1, TREK-2, and TRAAK) are important for mechanical and thermal nociception. However, the mechanisms underlying their gating by membrane stretch remain controversial. Here we use molecular dynamics simulations to examine their behavior in a lipid bilayer. We show that TREK-2 moves from the "down" to "up" conformation in direct response to membrane stretch, and examine the role of the transmembrane pressure profile in this process. Furthermore, we show how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. Finally, we present functional studies that demonstrate why direct pore block by lipid tails does not represent the principal mechanism of mechanogating. Overall, this study provides a dynamic structural insight into K2P channel mechanosensitivity and illustrates how the structure of a eukaryotic mechanosensitive ion channel responds to changes in forces within the bilayer. |
| spellingShingle | Aryal, P Jarerattanachat, V Clausen, M Schewe, M McClenaghan, C Argent, L Conrad, L Dong, Y Pike, A Carpenter, E Baukrowitz, T Sansom, M Tucker, S Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title | Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title_full | Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title_fullStr | Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title_full_unstemmed | Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title_short | Bilayer-Mediated Structural Transitions Control Mechanosensitivity of the TREK-2 K2P Channel. |
| title_sort | bilayer mediated structural transitions control mechanosensitivity of the trek 2 k2p channel |
| work_keys_str_mv | AT aryalp bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT jarerattanachatv bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT clausenm bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT schewem bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT mcclenaghanc bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT argentl bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT conradl bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT dongy bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT pikea bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT carpentere bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT baukrowitzt bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT sansomm bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel AT tuckers bilayermediatedstructuraltransitionscontrolmechanosensitivityofthetrek2k2pchannel |