6AVE

Structure of an acid sensing ion channel in a resting state at high pH

Summary for 6AVE

• Entry DOI: 10.2210/pdb6ave/pdb
• Related: 5WKU 5WKV 5WKX 5WKY
• EMDB information: 7009
• Descriptor: Acid-sensing ion channel 1, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: ion channel, asic, asic1a, sodium channel, transport protein, membrane protein
• Biological source: Gallus gallus (Chicken)
• Total number of polymer chains: 3
• Total formula weight: 181568.22

Authors

Yoder, N.,Yoshioka, C.,Gouaux, E. (deposition date: 2017-09-02, release date: 2018-03-21, Last modification date: 2024-10-30)

Primary citation

Yoder, N.,Yoshioka, C.,Gouaux, E.
Gating mechanisms of acid-sensing ion channels.
Nature, 555:397-401, 2018

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 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.

PubMed: 29513651
DOI: 10.1038/nature25782

Experimental method

ELECTRON MICROSCOPY (3.7 Å)