3u0z

Tetramerization dynamics of the C-terminus underlies isoform-specific cAMP-gating in HCN channels

spinqualitylabelsall models 3u0z, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3u0z is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: CMP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function HCN1_MOUSE Hyperpolarization-activated ion channel exhibiting weak selectivity for potassium over sodium ions. Contributes to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP, and at 10-100 times higher concentrations, also by cGMP. May mediate responses to sour stimuli. Publication Abstract from PubMed HCN channels are dually activated by hyperpolarization and binding of cAMP to their cyclic nucleotide binding domain (CNBD). HCN isoforms respond differently to cAMP: binding of cAMP shifts activation of HCN2 and HCN4 by 17 mV, but that of HCN1 by only 2-4 mV. To explain the peculiarity of HCN1 we solved the crystal structures and performed a biochemical-biophysical characterization of the C-terminal domain (C linker + CNBD) of the three isoforms. Our main finding is that tetramerization of the C-terminal domain of HCN1 occurs at basal cAMP concentrations while those of HCN2 and HCN4 require cAMP saturating levels. Therefore, HCN1 responds less markedly than HCN2 and HCN4 to cAMP increase because its CNBD is already partly tetrameric. This is confirmed by voltage clamp experiments showing that the right-shifted position of V1/2 in HCN1 is correlated with its propensity to tetramerize in vitro. These data underscore that ligand-induced CNBD tetramerization removes tonic inhibition from the pore of HCN channels. Tetramerization dynamics of the C-terminal domain underlies isoform-specific cAMP-gating in Hyperpolarization-activated Cyclic Nucleotide gated channels.,Lolicato M, Nardini M, Gazzarrini S, Moeller S, Bertinetti D, Herberg FW, Bolognesi M, Martin H, Fasolini M, Bertrand JA, Arrigoni C, Thiel G, Moroni A J Biol Chem. 2011 Oct 17. PMID:22006928 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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