Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in the control of pacemaking in the heart and repetitive firing in neurons. In HCN channels, the intracellular cyclic nucleotide-binding domain (CNBD) is connected to the transmembrane portion of the channel (TMPC) through a helical domain, the C-linker. Although this domain is critical for mechanical signal transduction, the conformational dynamics in the C-linker that transmit the nucleotide-binding signal to the HCN channel pore are unknown. Here, we use linear response theory to analyze conformational changes in the C-linker of the human HCN1 protein, which couple cAMP binding in the CNBD with gating in the TMPC. By applying a force to the tip of the so-called "elbow" of the C-linker, the coarse-grained calculations recapitulate the same conformational changes triggered by cAMP binding in experimental studies. Furthermore, in our simulations, a displacement of the C-linker parallel to the membrane plane (i.e. horizontally) induced a rotational movement resulting in a distinct tilting of the transmembrane helices. This movement, in turn, increased the distance between the voltage-sensing S4 domain and the surrounding transmembrane domains and led to a widening of the intracellular channel gate. In conclusion, our computational approach, combined with experimental data, thus provides a more detailed understanding of how cAMP binding is mechanically coupled over long distances to promote voltage-dependent opening of HCN channels.

Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel / C. Gross, A. Saponaro, B. Santoro, A. Moroni, G. Thiel, K. Hamacher. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 293:33(2018 Aug 17), pp. 12908-12918.

Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel

A. Saponaro;A. Moroni;
2018

Abstract

Hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels play a critical role in the control of pacemaking in the heart and repetitive firing in neurons. In HCN channels, the intracellular cyclic nucleotide-binding domain (CNBD) is connected to the transmembrane portion of the channel (TMPC) through a helical domain, the C-linker. Although this domain is critical for mechanical signal transduction, the conformational dynamics in the C-linker that transmit the nucleotide-binding signal to the HCN channel pore are unknown. Here, we use linear response theory to analyze conformational changes in the C-linker of the human HCN1 protein, which couple cAMP binding in the CNBD with gating in the TMPC. By applying a force to the tip of the so-called "elbow" of the C-linker, the coarse-grained calculations recapitulate the same conformational changes triggered by cAMP binding in experimental studies. Furthermore, in our simulations, a displacement of the C-linker parallel to the membrane plane (i.e. horizontally) induced a rotational movement resulting in a distinct tilting of the transmembrane helices. This movement, in turn, increased the distance between the voltage-sensing S4 domain and the surrounding transmembrane domains and led to a widening of the intracellular channel gate. In conclusion, our computational approach, combined with experimental data, thus provides a more detailed understanding of how cAMP binding is mechanically coupled over long distances to promote voltage-dependent opening of HCN channels.
English
HCN1 channel; anisotropic network model; cAMP dependent gating; computational biology; cyclic AMP (cAMP); linear response theory; potassium channel; protein conformation; protein dynamic
Settore BIO/09 - Fisiologia
Settore BIO/04 - Fisiologia Vegetale
Articolo
Esperti anonimi
Pubblicazione scientifica
   Noninvasive Manipulation of Gating in Ion Channels
   noMAGIC
   EUROPEAN COMMISSION
   H2020
   695078
17-ago-2018
American Society for Biochemistry and Molecular Biology
293
33
12908
12918
11
Pubblicato
Periodico con rilevanza internazionale
pubmed
Aderisco
info:eu-repo/semantics/article
Mechanical transduction of cytoplasmic-to-transmembrane-domain movements in a hyperpolarization-activated cyclic nucleotide-gated cation channel / C. Gross, A. Saponaro, B. Santoro, A. Moroni, G. Thiel, K. Hamacher. - In: THE JOURNAL OF BIOLOGICAL CHEMISTRY. - ISSN 0021-9258. - 293:33(2018 Aug 17), pp. 12908-12918.
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Prodotti della ricerca::01 - Articolo su periodico
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Article (author)
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C. Gross, A. Saponaro, B. Santoro, A. Moroni, G. Thiel, K. Hamacher
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/585383
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