Porro, Alessandro ; Saponaro, Andrea ; Castelli, Roberta ; Introini, Bianca ; Hafez Alkotob, Anahita ; Ranjbari, Golnaz ; Enke, Uta ; Kusch, Jana ; Benndorf, Klaus ; Santoro, Bina ; DiFrancesco, Dario ; Thiel, Gerhard ; Moroni, Anna (2024)
A high affinity switch for cAMP in the HCN pacemaker channels.
In: Nature communications, 15 (1)
doi: 10.1038/s41467-024-45136-y
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
Binding of cAMP to Hyperpolarization activated cyclic nucleotide gated (HCN) channels facilitates pore opening. It is unclear why the isolated cyclic nucleotide binding domain (CNBD) displays in vitro lower affinity for cAMP than the full-length channel in patch experiments. Here we show that HCN are endowed with an affinity switch for cAMP. Alpha helices D and E, downstream of the cyclic nucleotide binding domain (CNBD), bind to and stabilize the holo CNBD in a high affinity state. These helices increase by 30-fold cAMP efficacy and affinity measured in patch clamp and ITC, respectively. We further show that helices D and E regulate affinity by interacting with helix C of the CNBD, similarly to the regulatory protein TRIP8b. Our results uncover an intramolecular mechanism whereby changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels, adding another layer to the complex regulation of their activity.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2024 |
| Autor(en): | Porro, Alessandro ; Saponaro, Andrea ; Castelli, Roberta ; Introini, Bianca ; Hafez Alkotob, Anahita ; Ranjbari, Golnaz ; Enke, Uta ; Kusch, Jana ; Benndorf, Klaus ; Santoro, Bina ; DiFrancesco, Dario ; Thiel, Gerhard ; Moroni, Anna |
| Art des Eintrags: | Bibliographie |
| Titel: | A high affinity switch for cAMP in the HCN pacemaker channels |
| Sprache: | Englisch |
| Publikationsjahr: | 29 Januar 2024 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Nature communications |
| Jahrgang/Volume einer Zeitschrift: | 15 |
| (Heft-)Nummer: | 1 |
| DOI: | 10.1038/s41467-024-45136-y |
| Kurzbeschreibung (Abstract): | Binding of cAMP to Hyperpolarization activated cyclic nucleotide gated (HCN) channels facilitates pore opening. It is unclear why the isolated cyclic nucleotide binding domain (CNBD) displays in vitro lower affinity for cAMP than the full-length channel in patch experiments. Here we show that HCN are endowed with an affinity switch for cAMP. Alpha helices D and E, downstream of the cyclic nucleotide binding domain (CNBD), bind to and stabilize the holo CNBD in a high affinity state. These helices increase by 30-fold cAMP efficacy and affinity measured in patch clamp and ITC, respectively. We further show that helices D and E regulate affinity by interacting with helix C of the CNBD, similarly to the regulatory protein TRIP8b. Our results uncover an intramolecular mechanism whereby changes in binding affinity, rather than changes in cAMP concentration, can modulate HCN channels, adding another layer to the complex regulation of their activity. |
| ID-Nummer: | pmid:38287019 |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Biologie der Algen und Protozoen |
| Hinterlegungsdatum: | 06 Feb 2024 07:41 |
| Letzte Änderung: | 06 Feb 2024 09:27 |
| PPN: | 515292311 |
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| Suche nach Titel in: | TUfind oder in Google |
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