RSS

PDB:2QTS

Protein Name

Acid sensing ion channel, ASIC1

Species

Chicken

Biological Context

Although extracellular pH is usually kept neutral under the physiological conditions, it may be sometimes disrupted and our tissues suffer from lower pH. The acidification triggers some sensory signals; acidosis after ischemia or inflammation induces pain and acidic substrates transmit sour taste. Such sensory signals are mediated by acid sensing ion channel (ASIC), a ligand-gated, cation-selective ion channel activated by proton. ASIC is mainly localized on sensory neurons and is involved in detection and processing of sensory information.

Structure Description

2qts2qts_x2qts_y

ASIC1 is a trimeric channel in which each subunit of ASIC1 folds like “an upright forearm and clenched hand”. The extracellular domain, linker and transmembrane domain correspond to the hand, wrist and forearm respectively (fig1 left).

The most characteristic feature in an ASIC1 subunit is the extracellular domain that protrudes by as much as 80 Å from the membrane plane. The extracellular domain is divided into thumb, finger, knuckle, palm and β ball parts (fig1 right). Proton sensor locates within the negative charged “pocket” formed by two different subunits. As shown in fig2, four carboxyl-carboxylate interactions between the side chains of Asp or Glu are considered to be important for proton sensing. Because the distances of these interactions are between 2.8-3.0 Å in this ASIC1, at least one of carboxyl groups must be protonated to keep this conformation. Therefore, pH perturbation would change the conformation of extracellular domain and subsequent channel activity. Furthermore, one chloride ion in the pocket would be involved in the regulation of channel activity.

fig1 fig2
fig1. Overall structure of ASIC1
Left : Structure of homotrimeric ASIC1. The region inside the dotted square is shown in fig2. Right:Structure of monomeric ASIC1.
fig3
fig2. Four interactions between acidic aminoacid residues in the proton sensor of extracellular domain.
Four interactions are Asp238 (on finger in yellow subunit)-Asp350 (on thumb in yellow subunit), Glu239 (on finger in yellow subunit)-Asp346 (on thumb in yellow subunit), Glu220 (on palm in red subunit)-Asp408 (on palm in red subunit) and Glu80 (on palm in red subunit)-Glu417 (on palm in red subunit).A chloride ion (green sphere) is accomodated in this region.

The pore is formed by the hour-glass like transmembrane domain containing six helices (fig3). This ASIC is the desensitized state (inactivated state immediate after proton activation) and does not accommodate any ion in the pore. An ~30° kink at Gly435 of transmembrane helix TM2 helps the formation of the occlusion of Leu440 side chains. Gly-Ala-Ser motif near the Gly435, which plays an important role in the ion selectivity of ASIC, adopts a helical conformation that is completely different from flexible conformation of Gly-Tyr-Gly motif in the potassium channel selectivity filter.

fig4
fig3. Structure in the transmembrane domain. Only two subunits are shown to visualize the pore structure.

Protein Data Bank (PDB)

References

Source

Jasti, J. Furukawa, H. Gonzales, E.B. Gouaux, E.; "Structure of acid-sensing ion channel 1 at 1.9A resolution and low pH"; Nature; (2007) 449:316-323 PubMed:17882215.

Others

author: Daisuke Ino


Japanese version:PDB:2QTS