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

Saponaro, Andrea and Pauleta, Sofia R. and Cantini, Francesca and Matzapetakis, Manolis and Hammann, Christian and Donadoni, Chiara and Hu, Lei and Thiel, Gerhard and Banci, Lucia and Santoro, Bina and Moroni, Anna (2014):
Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.
In: Proceedings of the National Academy of Sciences of the United States of America, pp. 14577-14582, 11, (40), ISSN 1091-6490, [Article]

Abstract

cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.

Item Type: Article
Erschienen: 2014
Creators: Saponaro, Andrea and Pauleta, Sofia R. and Cantini, Francesca and Matzapetakis, Manolis and Hammann, Christian and Donadoni, Chiara and Hu, Lei and Thiel, Gerhard and Banci, Lucia and Santoro, Bina and Moroni, Anna
Title: Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function.
Language: English
Abstract:

cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD.

Journal or Publication Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 11
Number: 40
Divisions: 10 Department of Biology
10 Department of Biology > Plant Membrane Biophysics
Date Deposited: 16 Sep 2014 09:41
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