Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control spontaneous electrical activity in heart and brain. Binding of cAMP to the cyclic nucleotide-binding domain (CNBD) facilitates channel opening by relieving a tonic inhibition exerted by the CNBD. Despite high resolution structures of the HCN1 channel in the cAMP bound and unbound states, the structural mechanism coupling ligand binding to channel gating is unknown. Here we show that the recently identified helical HCN-domain (HCND) mechanically couples the CNBD and channel voltage sensing domain (VSD), possibly acting as a sliding crank that converts the planar rotational movement of the CNBD into a rotational upward displacement of the VSD. This mode of operation and its impact on channel gating are confirmed by computational and experimental data showing that disruption of critical contacts between the three domains affects cAMP- and voltage-dependent gating in three HCN isoforms.
All data analyzed during this study are included in the manuscript and supporting files. Source data files for LRT analysis and MD simulations have been deposited in Dyrad and are available at doi:10.5061/dryad.rn85375
Date from: The HCN domain couples voltage gating and cAMP response in Hyperpolarization-activated Cyclic Nucleotide-gated channelsDryad Digital Repository, 10.5061/dryad.rn85375.
- Anna Moroni
- Anna Moroni
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- László Csanády, Semmelweis University, Hungary
© 2019, Porro et al.
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