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Akimoto, M.* ; Zhang, Z.* ; Boulton, S.* ; Selvaratnam, R.* ; van Schouwen, B.* ; Gloyd, M.* ; Accili, E.A.* ; Lange, O.F. ; Melacini, G.*

A mechanism for the auto-inhibition of Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel opening and its relief by cAMP.

J. Biol. Chem. 289, 22205-22220 (2014)
Verlagsversion DOI PMC
Open Access Gold
Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels control neuronal and cardiac electrical rhythmicity. There are four homologous isoforms (HCN1-4) sharing a common multi-domain architecture that includes an N-terminal trans-membrane tetrameric ion channel followed by a cytoplasmic "C-linker", which connects a more distal cAMP-binding domain (CBD) to the inner pore. Channel opening is primarily stimulated by transmembrane elements that sense membrane hyperpolarization, while cAMP reduces the voltage required for HCN activation by promoting tetramerization of the intracellular C-linker, which in turn relieves auto-inhibition of the inner pore gate. Although binding of cAMP has been proposed to relieve auto-inhibition by affecting the structure of the C-linker and CBD, the nature and extent of these cAMP-dependent changes remain limitedly explored. Here, we used NMR to probe the changes caused by the binding of cAMP and of cCMP, a partial agonist, to the apo CBD of HCN4. Our data indicate that the CBD exists in a dynamic two-state equilibrium, whose position as gauged by NMR chemical shifts correlates with the V1/2 voltage measured through electrophysiology. In the absence of cAMP, the most populated CBD state leads to steric clashes with the activated or "tetrameric" C-linker, which becomes energetically unfavoured. The steric clashes of the apo tetramer are eliminated either by cAMP-binding, which selects for a CBD state devoid of steric clashes with the tetrameric C-linker and facilitates channel opening, or by a transition of apo HCN to monomers or dimer of dimers, in which the C-linker becomes less structured and channel opening is not facilitated.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Hcn ; Intrinsically Disordered Proteins (idps) ; Allosteric Regulation ; Allostery ; Camp-binding Domain (cbd) ; Ccmp ; Cyclic Amp (camp) ; Nuclear Magnetic Resonance (nmr) ; Protein Conformation ; Signaling; Nmr Chemical-shifts; Protein-kinase-a; Pacemaker Channels; Structural Basis; Binding Domain; Conformational-changes; Dependent Activation; Structure Reveals; Terminal Region; Ion Channels
Sprache englisch
Veröffentlichungsjahr 2014
HGF-Berichtsjahr 2014
ISSN (print) / ISBN 0021-9258
e-ISSN 1083-351X
Zeitschrift Journal of Biological Chemistry, The
Quellenangaben Band: 289, Heft: 32, Seiten: 22205-22220 Artikelnummer: , Supplement: ,
Verlag American Society for Biochemistry and Molecular Biology
Verlagsort Bethesda
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-003
PubMed ID 24878962
DOI 10.1074/jbc.M114.572164
WOS ID WOS:000340593500035
Scopus ID 84905836722
Erfassungsdatum 2014-06-26
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