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| Title | Gating mechanisms of acid-sensing ion channels. |
|---|---|
| Journal, issue, pages | Nature, Vol. 555, Issue 7696, Page 397-401, Year 2018 |
| Publish date | Mar 15, 2018 |
 Authors | Nate Yoder / Craig Yoshioka / Eric Gouaux /  |
| PubMed Abstract | Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed ...Acid-sensing ion channels (ASICs) are trimeric, proton-gated and sodium-selective members of the epithelial sodium channel/degenerin (ENaC/DEG) superfamily of ion channels and are expressed throughout vertebrate central and peripheral nervous systems. Gating of ASICs occurs on a millisecond time scale and the mechanism involves three conformational states: high pH resting, low pH open and low pH desensitized. Existing X-ray structures of ASIC1a describe the conformations of the open and desensitized states, but the structure of the high pH resting state and detailed mechanisms of the activation and desensitization of the channel have remained elusive. Here we present structures of the high pH resting state of homotrimeric chicken (Gallus gallus) ASIC1a, determined by X-ray crystallography and single particle cryo-electron microscopy, and present a comprehensive molecular mechanism for proton-dependent gating in ASICs. In the resting state, the position of the thumb domain is further from the three-fold molecular axis, thereby expanding the 'acidic pocket' in comparison to the open and desensitized states. Activation therefore involves 'closure' of the thumb into the acidic pocket, expansion of the lower palm domain and an iris-like opening of the channel gate. Furthermore, we demonstrate how the β11-β12 linkers that demarcate the upper and lower palm domains serve as a molecular 'clutch', and undergo a simple rearrangement to permit rapid desensitization. |
 External links | Nature / PubMed:29513651 / PubMed Central |
| Methods | EM (single particle) / X-ray diffraction |
| Resolution | 2.95 - 3.7 Å |
| Structure data | EMDB-7009, PDB-6ave:  PDB-5wku:  PDB-5wkv: |
| Chemicals |  ChemComp-NAG:  ChemComp-CL:  ChemComp-BA:  ChemComp-CA: |
| Source |
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 Keywords |  TRANSPORT PROTEIN / Ion channel / ASIC / ASIC1a / Sodium channel / MEMBRANE PROTEIN |
