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Real-time visualization of conformational changes within single MloK1 cyclic nucleotide-modulated channels

M. Rangl,A. Miyagi,J. Kowal,H. Stahlberg,C. Nimigean,S. Scheuring

Published 2016 in Nature Communications

ABSTRACT

Eukaryotic cyclic nucleotide-modulated (CNM) ion channels perform various physiological roles by opening in response to cyclic nucleotides binding to a specialized cyclic nucleotide-binding domain. Despite progress in structure-function analysis, the conformational rearrangements underlying the gating of these channels are still unknown. Here, we image ligand-induced conformational changes in single CNM channels from Mesorhizobium loti (MloK1) in real-time, using high-speed atomic force microscopy. In the presence of cAMP, most channels are in a stable conformation, but a few molecules dynamically switch back and forth (blink) between at least two conformations with different heights. Upon cAMP depletion, more channels start blinking, with blinking heights increasing over time, suggestive of slow, progressive loss of ligands from the tetramer. We propose that during gating, MloK1 transitions from a set of mobile conformations in the absence to a stable conformation in the presence of ligand and that these conformations are central for gating the pore. Some ion channels are modulated by binding of cyclic nucleotide to a cyclic nucleotide-binding domain. Here, the authors use high-speed atomic force microscopy to directly monitor the conformational changes induced by ligand binding to a cyclic nucleotide-modulated channel from Mesorhizobium loti.

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