RESUMEN
Otopetrin (Otop) proteins were recently found to function as proton channels, with Otop1 revealed to be the sour taste receptor in mammals. Otop proteins contain twelve transmembrane segments (S1-S12) which are divided into structurally similar N and C domains. The mechanisms by which Otop channels sense extracellular protons to initiate gating and conduct protons once the channels are activated remains largely elusive. Here we show that two extracellular loops are playing key roles in human Otop1 channel function. We find that residue H229 in the S5-S6 loop is critical for proton sensing of Otop1. Further, our data reveal that the S11-12 loop is structurally and functionally essential for the Otop1 channel and that residue D570 in this loop regulates proton permeation into the pore formed by the C domain. This study sheds light on the molecular mechanism behind the structure and function of this newly identified ion channel family.
