Ion channels

Abstract:

The flux of ions through a channel is most commonly regulated by changes that result in steric occlusion of its pore. However, ion permeation can also be prevented by formation of a desolvation barrier created by hydrophobic residues that line the pore. As a result of relatively minor structural changes, confined hydrophobic regions in channels may undergo transitions between wet and dry states to gate the pore closed without physical constriction of the permeation pathway. This concept is referred to as hydrophobic gating, and many examples of this process have been demonstrated. However, the term is also now being used in a much broader context that often deviates from its original meaning. In this Viewpoint, we explore the formal definition of a hydrophobic gate, discuss examples of this process compared with other gating mechanisms that simply exploit hydrophobic residues and/or lipids in steric closure of the pore, and describe the best practice for identification of a hydrophobic gate.

Abstract:

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K⁺ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the ‘X-gate’, a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K⁺ channels and their link with sleep apnea but also identify possible therapeutic strategies.

Abstract:

Amino acid transporters play a key role controlling the flow of nutrients across the lysosomal membrane and regulating metabolism in the cell. Mutations in the gene encoding the transporter cystinosin result in cystinosis, an autosomal recessive metabolic disorder characterised by the accumulation of cystine crystals in the lysosome. Cystinosin is a member of the PQ-loop family of solute carrier (SLC) transporters and uses the proton gradient to drive cystine export into the cytoplasm. However, the molecular basis for cystinosin function remains elusive, hampering efforts to develop novel treatments for cystinosis and understand the mechanisms of ion driven transport in the PQ-loop family. To address these questions, we present the crystal structures of cystinosin from Arabidopsis thaliana in both apo and cystine bound states. Using a combination of in vitro and in vivo based assays, we establish a mechanism for cystine recognition and proton coupled transport. Mutational mapping and functional characterisation of human cystinosin further provide a framework for understanding the molecular impact of disease-causing mutations.