Identifies the molecular interface between the eag domain and CNBHD of the hERG channel, providing mechanistic insight into how disease-associated mutations like R56Q may disrupt channel gating.
Does not yet inform clinical management of hERG channelopathies; extends molecular mapping of disease mutations for future mechanistic studies.
The gating of the hERG channel is regulated by its eag domain through molecular interaction with either the cyclic nucleotide-binding homology domain (CNBHD) or the linker between transmembrane segments 4 and 5. Our NMR study on the purified CNBHD demonstrated that it contains nine β-strands and does not bind cAMP. We show that the eag domain binds to the CBND through an interface containing several disease-associated mutations. The N-terminal cap domain and R56 in the eag domain are important for the interaction with the CNBHD. Residues from the CNBHD that were affected by the interaction with the eag domain were also identified. A R56Q mutation does not cause major structural changes in the eag domain and showed reduced interaction with the CNBHD.
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Li et al. (2014) studied this question.
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