ASOR is a chloride channel that appears to be ubiquitously expressed in vertebrate cells and that needs acidic extracellular pH for activation. ASOR is important under pathological conditions, but its physiological roles remain enigmatic although its wide expression pattern suggests that it is very important. Although identified in electrophysiological studies more than 10 years ago, the proteins constituting this channel has remained unknown. Using a genome-wide siRNA screen with a sophisticated functional read-out, we recently identified TMEM206 proteins as constituting this channel. TMEM206 has two transmembrane domains, both of which appear to line the ion-selective pore as determined by mutagenesis. All tested vertebrate orthologs, including those from lizard or acid-insensitive naked mole rats, display a strong pH-dependence. Our molecular identification of TMEM206/ASOR channels finally open the door to investigate the biological function of this enigmatic, but apparently important chloride channel.
Ullrich et al., eLife (2019) Research Highlight
In collaboration with Steve Long (Sloan Kettering, New York) we determined the mechanism of channel opening by acidic pH. Cryo-EM structures showed unexpectedly large shifts of the transmembrane domains in the trimeric ASOR channels with acidic pH. These were drven by protons allowing three pairs of extracellular acidic residdues to closely approach each other.