Structural highlights
Publication Abstract from PubMed
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.
Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel.,Schmidpeter PAM, Rheinberger J, Nimigean CM Nat Commun. 2020 Dec 16;11(1):6401. doi: 10.1038/s41467-020-20104-4. PMID:33328472[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Schmidpeter PAM, Rheinberger J, Nimigean CM. Prolyl isomerization controls activation kinetics of a cyclic nucleotide-gated ion channel. Nat Commun. 2020 Dec 16;11(1):6401. doi: 10.1038/s41467-020-20104-4. PMID:33328472 doi:http://dx.doi.org/10.1038/s41467-020-20104-4
