Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1.
Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1-S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an 'open' conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels.
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Julia
J
Kowal
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Mohamed
M
Chami
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Paul
P
Baumgartner
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Marcel
M
Arheit
1] [2].
Po-Lin
PL
Chiu
U1006 INSERM, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13009 Marseille, France.
Martina
M
Rangl
U1006 INSERM, Aix-Marseille Université, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13009 Marseille, France.
Simon
S
Scheuring
1] Forschungszentrum Jülich, Institute of Complex Systems, ICS-6: Structural Biochemistry, 52425 Jülich, Germany [2] Department of Physics, Heinrich-Heine University Düsseldorf, 40225 Düsseldorf, Germany.
Gunnar F
GF
Schröder
Departments of Anesthesiology, Physiology and Biophysics, and Biochemistry, Weill Cornell Medical College, 1300 York Ave, New York, New York 10065, USA.
Crina M
CM
Nimigean
Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland.
Henning
H
Stahlberg
D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D020285:Cryoelectron Microscopy; D018360:Crystallography, X-Ray; D000242:Cyclic AMP / Q000378:metabolism; D015640:Ion Channel Gating; D008024:Ligands; D059128:Mesorhizobium / Q000378:metabolism*; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism
D001426:Bacterial Proteins; D008024:Ligands; D015221:Potassium Channels; D000242:Cyclic AMP