Roe of dynamics in the autoinhibition and activation of the hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels

Bryan Vanschouwen, Madoka Akimoto, Maryam Sayadi, Federico Fogolari, Giuseppe Melacini

研究成果: Article査読

16 被引用数 (Scopus)

抄録

The hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes. Cyclic AMP allosterically modulates HCN through the cAMP-dependent formation of a tetrameric gating ring spanning the intracellular region (IR) of HCN, to which cAMP binds. Although the apo versus holo conformational changes of the cAMP-binding domain (CBD) have been previously mapped, only limited information is currently available on the HCN IR dynamics, which have been hypothesized to play a critical role in the cAMP-dependent gating of HCN. Here, using molecular dynamics simulations validated and complemented by experimental NMR and CD data, we comparatively analyze HCN IR dynamics in the four states of the thermodynamic cycle arising from the coupling between cAMP binding and tetramerization equilibria. This extensive set of molecular dynamics trajectories captures the active-to-inactive transition that had remained elusive for other CBDs, and it provides unprecedented insight on the role of IR dynamics inHCNautoinhibition and its release by cAMP. Specifically, the IR tetramerization domain becomes more flexible in the monomeric states, removing steric clashes that the apo-CDB structure would otherwise impose. Furthermore, the simulations reveal that the active/inactive structural transition for the apo-monomeric CBD occurs through a manifold of pathways that are more divergent than previously anticipated. Upon cAMP binding, these pathways become disallowed, pre-confining the CBD conformational ensemble to a tetramer-compatible state. This conformational confinement primes the IR for tetramerization and thus provides a model of how cAMP controls HCN channel gating.

本文言語English
ページ(範囲)17642-17654
ページ数13
ジャーナルJournal of Biological Chemistry
290
29
DOI
出版ステータスPublished - 2015 7 17

ASJC Scopus subject areas

  • 生化学
  • 分子生物学
  • 細胞生物学

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