“KCNH Channel Regulation: A Structural Point of View”
Abstract:
The KCNH voltage dependent potassium channels are key regulators of cellular excitability, involved in cardiac long QT syndrome type 2 (LQTS2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels, and include an amino-terminal eag domain, composed from a Per-Arnt-Sim (PAS) module and a PAS-cap region, and a carboxy-terminal cyclic nucleotide-binding homology domain (CNBHD), connected to the pore domain through a C-linker domain. These specialized intracellular domains are the site of many disease-causing mutations and bestow unique gating and regulation on KCNH channels. Using fluorescence, x-ray crystallography and electrophysiological approaches, we determined and validated the structure of the intracellular complex of mEAG1 channel. Harboring many LQTS2 and cancer-associated mutations, the eag domain-CNBHD interface involves three important regions: (i) the “intrinsic ligand” motif, a unique structural feature of the CNBHD; (ii) the post-CNBHD region, known to mediate EAG channels regulation by a variety of cellular signaling events; and finally, (iii) the PAS-cap region, which constitutes the first 25 amino acids of the eag domain, and forms a highly conserved amphipathic helix (αCAP). Together, this work provides a detailed physiological and pathophysiological description of the intracellular domain of the KCNH family.
מארחת: פרופ”ח פיליפה מלמד
Dr. Yoni Haitin, Department of Physiology and Biophysics, University of Washington, Seattle.
