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Structure of a Voltage-Gated Ion Channel Print
Tuesday, 14 February 2012 16:37


Researchers from the University of Washington and the Collaborative Crystallography program at the Berkeley Center for Structural Biology used ALS Beamline 8.2.1 to solve the structure of a voltage-gated ion channel. This type of protein that controls the flow of ions across a cell membrane in response to electrical potential. Voltage-gated ion channels are critical in many biological functions, such as regulating electrical signals in heart and nerve cells. Damage to these cells can lead to tumor cell proliferation.

The KCNH family of ion channels contains an intracellular carboxy-terminal region connected to the channel pore by a C-linker protein. These regions are important for channel trafficking and function. The carboxy-terminal domain has high homology to many nucleotide-binding domains; however, since this protein family is not regulated by nucleotide binding, the function of this intracellular domain was not well understood prior to this study. The structure of the carboxy-terminal region of a KCNH channel from zebrafish was solved, showing that the ligand-binding pocket has a negatively charged electrostatic profile. This makes it an unfavorable site for binding by negatively charged nucleotides, which may help explain its nucleotide independence. Changing a key amino acid in the region shifts the voltage dependence of the channel, suggesting that the region may act as an intrinsic regulatory element.

Three-dimensional representation of the C-linker protein, which connects the intracellular carboxy-terminal region to the channel pore, in a zebrafish KCNH ion channel.



Topology of channels in a member of the KCNH family of proteins in zebrafish. This cartoon shows two of the four subunits contained in the channel. The pore-forming loop and S5-S6 transmembrane domains are grey. The N-terminal alpha-helix and Per-Arnt-Sim domain are magenta. The 'elbow' and 'shoulder' regions of the C-linker are represented by the red and peach cylinders, respectively. The alphaC-helix, represented by a cylinder, is green and the rest of the cyclic-nucleotide-binding homology domain is blue.



Work performed on ALS Beamline 8.2.1.

Citation: T.I. Brelidze, A.E. Carlson, B. Sankaran, W.N. Zagotta, "Structure of the carboxy-terminal region of a KCNH channel," Nature 481, 530 (2012). doi:10.1038/nature10735