Structure of Connexin26 from Lepidosiren paradoxa

Abstract

Connexin gap junction channels enable the direct exchange of molecules and ions between cells. Channel opening is regulated by various physiological stimuli. Human connexin26 gap junction channels close in response to elevated levels of CO2 in a process that is independent of pH, with structures demonstrating a [CO2]-dependent conformational change. Cx26 from the lungfish, Lepidosiren paradoxa is also CO2 sensitive. Here we solve its structure at high [CO2]. We observe an open conformation of the protein where the N-terminal helix that influences the aperture of the pore is pulled away from the centre. This conformation is stabilised by the presence of a detergent binding between TM3 and TM4 that would prevent the conformational changes necessary to close the protein upon exchange to high [CO2]. The structure supports a mechanism in which the conformation of a motif shown to be important for CO2 sensitivity is correlated with the opening of the pore.