Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel

Philipp A. M. Schmidpeter, Jan Rheinberger and Crina M. Nimigean ()
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Philipp A. M. Schmidpeter: Weill Cornell Medicine, Department of Anesthesiology
Jan Rheinberger: Weill Cornell Medicine, Department of Anesthesiology
Crina M. Nimigean: Weill Cornell Medicine, Department of Anesthesiology

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract SthK, a cyclic nucleotide-modulated ion channel from Spirochaeta thermophila, activates slowly upon cAMP increase. This is reminiscent of the slow, cAMP-induced activation reported for the hyperpolarization-activated and cyclic nucleotide-gated channel HCN2 in the family of so-called pacemaker channels. Here, we investigate slow cAMP-induced activation in purified SthK channels using stopped-flow assays, mutagenesis, enzymatic catalysis and inhibition assays revealing that the cis/trans conformation of a conserved proline in the cyclic nucleotide-binding domain determines the activation kinetics of SthK. We propose that SthK exists in two forms: trans Pro300 SthK with high ligand binding affinity and fast activation, and cis Pro300 SthK with low affinity and slow activation. Following channel activation, the cis/trans equilibrium, catalyzed by prolyl isomerases, is shifted towards trans, while steady-state channel activity is unaffected. Our results reveal prolyl isomerization as a regulatory mechanism for SthK, and potentially eukaryotic HCN channels. This mechanism could contribute to electrical rhythmicity in cells.

Date: 2020
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DOI: 10.1038/s41467-020-20104-4

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