Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

Saponaro, Andrea; Pauleta, Sofia R.; Cantini, Francesca; Matzapetakis, Manolis; Hammann, Christian; Donadoni, Chiara; Hu, Lei; Thiel, Gerhard; Banci, Lucia; Santoro, Bina; Moroni, Anna

doi:10.1073/pnas.1410389111

Cited by 70 publications

(167 citation statements)

References 40 publications

(55 reference statements)

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“…For instance, our MD simulations correctly capture the quenching of dynamics of the C-terminal CBD ␣B-␣C helices upon cAMP binding to either the monomeric or tetrameric IR (Table 3 and Fig. 8), as determined previously by NMR, DEER, and fluorescence spectroscopy (17,(45)(46)(47). Furthermore, our MD simulations correctly predict that the N3A topology in the apo-monomer IR undergoes a transition from the "out" to the "in" orientation, in agreement a The peptide concentration was 0.1 mg/ml.…”

Section: Discussionsupporting

confidence: 70%

Role of Dynamics in the Autoinhibition and Activation of the Hyperpolarization-activated Cyclic Nucleotide-modulated (HCN) Ion Channels

VanSchouwen

Akimoto

Sayadi

et al. 2015

Journal of Biological Chemistry

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Background: Hyperpolarization-activated cyclic nucleotide-modulated (HCN) ion channels control rhythmicity in neurons and cardiomyocytes, but their regulatory mechanism is not fully understood. Results: Both tetramerization and cAMP binding reduce dynamics in the HCN intracellular region. Conclusion: Intracellular HCN dynamics are crucial for HCN autoinhibition and cAMP modulation. Significance: A full map of the changes in dynamics coupled to HCN gating is necessary to understand HCN regulation by cAMP.

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Section: Discussionsupporting

confidence: 70%

Role of Dynamics in the Autoinhibition and Activation of the Hyperpolarization-activated Cyclic Nucleotide-modulated (HCN) Ion Channels

VanSchouwen

Akimoto

Sayadi

et al. 2015

Journal of Biological Chemistry

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“…This region contains the so-called KHA domain at the very C terminus, but also a C-linker and a CNBHD (Marten and Hoshi, 1997). These two domains constitute, even in channels that are not regulated by binding of cyclic nucleotides, a key region for gating control (Lolicato et al, 2011;Saponaro et al, 2014;Whicher and MacKinnon, 2016). Also, the aforementioned KHA domain is a potential target for a modulation of gating.…”

Section: Discussionmentioning

confidence: 99%

Fusicoccin Activates KAT1 Channels by Stabilizing their Interaction with 14-3-3- Proteins

et al. 2017

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Plants acquire potassium (K + ) ions for cell growth and movement via regulated diffusion through K + channels. Here, we present crystallographic and functional data showing that the K + inward rectifier KAT1 (K + Arabidopsis thaliana 1) channel is regulated by 14-3-3 proteins and further modulated by the phytotoxin fusicoccin, in analogy to the H + -ATPase. We identified a 14-3-3 mode III binding site at the very C terminus of KAT1 and cocrystallized it with tobacco (Nicotiana tabacum) 14-3-3 proteins to describe the protein complex at atomic detail. Validation of this interaction by electrophysiology shows that 14-3-3 binding augments KAT1 conductance by increasing the maximal current and by positively shifting the voltage dependency of gating. Fusicoccin potentiates the 14-3-3 effect on KAT1 activity by stabilizing their interaction. Crystal structure of the ternary complex reveals a noncanonical binding site for the toxin that adopts a novel conformation. The structural insights underscore the adaptability of fusicoccin, predicting more potential targets than so far anticipated. The data further advocate a common mechanism of regulation of the proton pump and a potassium channel, two essential elements in K + uptake in plant cells.

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“…Comparison of the structures of the cGMP-bound TAX-4 C-linker/CNBD and an unbound HCN2 C-linker/CNBD 37 reveals marked conformational changes in both the CNBD and the C-linker in the unbound state (Fig. 5d).…”

Section: The Cyclic Nucleotide-binding Domain and C-linkermentioning

confidence: 99%

Structure of a eukaryotic cyclic-nucleotide-gated channel

Zhou

Wang

et al. 2017

Nature

129

166

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Summary Cyclic nucleotide-gated (CNG) channels are essential for vision and olfaction. They belong to the voltage-gated ion channel superfamily but their activities are controlled by intracellular cyclic nucleotides instead of transmembrane voltage. Here we report a 3.5 Å-resolution single-particle electron cryomicroscopy structure of a CNG channel from C. elegans in the cGMP-bound open state. The channel has an unusual voltage-sensor-like domain (VSLD), accounting for its deficient voltage dependence. A C-terminal linker connecting S6 and the cyclic nucleotide-binding domain interacts directly with both the VSLD and pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chains of a functionally important glutamate and three rings of backbone carbonyls. This structure provides a new framework for understanding mechanisms of ion permeation, gating and channelopathy of CNG channels and cyclic nucleotide modulation of related channels.

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Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

Cited by 70 publications

References 40 publications

Role of Dynamics in the Autoinhibition and Activation of the Hyperpolarization-activated Cyclic Nucleotide-modulated (HCN) Ion Channels

Role of Dynamics in the Autoinhibition and Activation of the Hyperpolarization-activated Cyclic Nucleotide-modulated (HCN) Ion Channels

Fusicoccin Activates KAT1 Channels by Stabilizing their Interaction with 14-3-3- Proteins

Structure of a eukaryotic cyclic-nucleotide-gated channel

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