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TitleGating mechanisms of acid-sensing ion channels.
Journal, issue, pagesNature, Vol. 555, Issue 7696, Page 397-401, Year 2018
Publish dateMar 15, 2018
AuthorsNate Yoder / Craig Yoshioka / Eric Gouaux /
PubMed AbstractAcid-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 linksNature / PubMed:29513651 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.95 - 3.7 Å
Structure data

7009

6ave

EMDB-7009, PDB-6ave:
Structure of an acid sensing ion channel in a resting state at high pH
Method: EM (single particle) / Resolution: 3.7 Å

PDB-5wku:
Structure of an acid sensing ion channel in a resting state with barium
Method: X-RAY DIFFRACTION / Resolution: 2.95 Å

PDB-5wkv:
Structure of an acid sensing ion channel in a resting state with calcium
Method: X-RAY DIFFRACTION / Resolution: 3.2 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-CL:
Unknown entry / Chloride

ChemComp-BA:
Unknown entry

ChemComp-CA:
Unknown entry

Source
  • Gallus (bird)
  • gallus gallus (chicken)
KeywordsTRANSPORT PROTEIN / Ion channel / ASIC / ASIC1a / Sodium channel / MEMBRANE PROTEIN

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