Mechanism Of Regulation Of Kef Channels By Chemically Diverse Glutathione Molecules

KTN (RCK) domains are ubiquitous, canonically dimeric, cytoplasmic regulatory domains that control the flux of K+ transporters and channels in response to cellular cues. We have determined the structures of the C-terminal KTN-bearing domain of KefC, bound alternately to the inhibitory ligand, reduced glutathione, or an activating glutathione adduct. Analysis of these structures reveals that the former stabilizes an inter-domain association between helix α2 from one KTN domain with helices α7/8 of the partnering chain. In contrast, activating glutathione conjugates disrupt this interaction. The resulting conformational change directly impacts the physical exposure of the KTN protein interaction interface that is critical to controlling ion flow through the pore. The elucidated mechanism explains both how subtle chemical differences in glutathione derivatives can have contrary affects on transporter function, as well as how chemically diverse adducts can all elicit activation of this system.