Featured Article - March 2012
Short description: A structure of an engineered potassium channel suggests a novel model for the gating mechanism.
Inwardly rectifying potassium (Kir) channels function in a wide range of cell types to regulate membrane excitability, and abnormal function is increasingly associated with disease states. The prokaryotic KirBac channels are homologs of the tetrameric eukaryotic Kir channels and have provided detailed structural insights into the molecular mechanisms of gating. Ion transport occurs when conformational changes in the large cytoplasmic domains (CTD) result in an open conformation of the bundle-crossing gate. Mechanistic insights depend on trapping KirBac channels in different gating conformations.
Tucker, Vénien-Bryan and colleagues have solved the structure of a functionally active mutant of KirBac3.1 in which an S129R substitution in the inner pore-lining helix (TM2) allowed the first observation of the gate in an apparently open conformation. Electrostatic and steric repulsion by the introduced arginine mimics the open state of the wild-type channel, as evidenced by an increase in intersubunit distance between the Tyr132 residues in TM2 that form the primary gate. In addition, the TM2 helix both bends at and rotates around the highly conserved G120 hinge residue while the outer TM1 helix is displaced outward. The TM2 rotation also causes an outward movement of the Leu124 residue that forms the secondary gate within the central cavity, resulting in an increased effective pore diameter.
Importantly, the structure challenges a recent model that suggests that a twist conformation of the CTD with respect to the pore is not ion-conductive. Since the active S129R mutant has both a twist conformation of the CTD and ion occupancy at all four potassium binding sites, the authors conclude that the structure represents an active state. They propose a gating model based on an intricate network of intra- and intersubunit contacts involving the C-linker between the CTD and TM2. Comparison with a closed non-twist structure highlights how the C-linker couples CTD twist movement to pore opening to stabilize the open state. The authors note that while the S129R structure may not be in a fully open conformation, comparison with an open structure of the KcsA potassium channel supports their model. The new structure extends our knowledge of the dynamics of KirBac channels during ion transport.
V.N. Bavro et al. Structure of a KirBac channel with an open bundle crossing indicates a mechanism for channel gating.
Nat. Struct. Mol. Biol. 19, 158-163 (2012). doi:10.1038/nsmb.2208