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PDBsum entry 2mpf
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Transport protein
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PDB id
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2mpf
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References listed in PDB file
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Key reference
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Title
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Structural basis for the mutual antagonism of camp and trip8b in regulating hcn channel function.
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Authors
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A.Saponaro,
S.R.Pauleta,
F.Cantini,
M.Matzapetakis,
C.Hammann,
C.Donadoni,
L.Hu,
G.Thiel,
L.Banci,
B.Santoro,
A.Moroni.
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Ref.
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Proc Natl Acad Sci U S A, 2014,
111,
14577-14582.
[DOI no: ]
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PubMed id
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Abstract
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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.
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