Editors' ChoiceStructural Biology

Almost Open

Sci. Signal.  18 Jun 2013:
Vol. 6, Issue 280, pp. ec141
DOI: 10.1126/scisignal.2004420

GIRK channels are G protein–activated K+ channels that are important for limiting heart rate and neuronal excitability. These channels are activated by the βγ subunits of G proteins, and the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) and Na+ ions are also regulators of channel activity (see Reuveny). Whorton and MacKinnon reported the crystal structure of residues 52 to 380 of mouse GIRK2 with the βγ subunit dimer that activates the channel. The crystal consists of four channel subunits, which form the conducting pore, each bound to one βγ dimer, one PIP2 molecule, and one Na+ ion. Comparison of this structure with that of GIRK2-PIP2 and that of a constitutively active mutant GIRK2 led the authors to propose that binding of the βγ subunits triggers channel twisting such that the pore, although not large enough to conduct hydrated K+ ions, is closer to the open conformation, thus increasing the likelihood of randomly occurring switches to the conducting conformation. This model is consistent with the bursting channel opening observed for these channels in electrophysiological studies. Whether all four channel subunits must interact with a βγ subunit in vivo to mediate channel regulation remains an open question.

M. R. Whorton, R. MacKinnon, X-ray structure of the mammalian GIRK2-βγ G-protein complex. Nature 498, 190–197 (2013). [PubMed]

E. Reuveny, Ion channel twists to open. Nature 498, 182–183 (2013). [PubMed]