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Proc Natl Acad Sci U S A
2005 Feb 22;1028:2742-7. doi: 10.1073/pnas.0408323102.
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The carboxyl-terminal region of cyclic nucleotide-modulated channels is a gating ring, not a permeation path.
Johnson JP
,
Zagotta WN
.
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The recent elucidation of the structure of the carboxyl-terminal region of the hyperpolarization-activated cyclic nucleotide-modulated (HCN2) channel has prompted us to investigate a curious feature of this structure in HCN2 channels and in the related CNGA1 cyclic nucleotide-gated (CNG) channels. The crystallized fragment of the HCN2 channel contains both the cyclic nucleotide-binding domain (CNBD) and the C-linker region, which connects the CNBD to the pore. At the center of the fourfold-symmetric structure is a tunnel that runs perpendicular to the membrane. The narrowest part of the tunnel is approximately 10 A in diameter and is lined by a ring of negatively charged amino acids: D487, E488, and D489. Many ion channels have "charge rings" that focus permeant ions at the mouth of the pore and increase channel conductance. We used nonstationary fluctuation analysis and single-channel recording, coupled with site-directed mutagenesis and cysteine modification, to determine whether this part of HCN and CNG channels might be an extension of the permeation pathway. Our results indicate that modifying charge-ring amino acids affects gating but not ion permeation in HCN2 and CNG channels. Thus, this portion of the channel is not an obligatory part of the ion path but instead acts as a "gating ring." The carboxyl-terminal region of these channels must hang below the pore much like the "hanging gondola" of voltage-gated potassium channels, but the permeation pathway must exit the protein before the level of the ring of charged amino acids.
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