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  • Nipavan Chiamvimonvat
    Correspondence
    Address reprint requests and correspondence: Dr Nipavan Chiamvimonvat, Department of Internal Medicine and Pharmacology, University of California, Davis, GBSF 6315, 451 Health Science Drive, Davis, CA 95616.
    Affiliations
    Department of Internal Medicine and Pharmacology, University of California, Davis, Davis, California
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Published:November 10, 2021DOI:https://doi.org/10.1016/j.hrthm.2021.11.011
      Harley et al (Proc Natl Acad Sci U S A 2021;118:e2108796118, PMID 34716268) investigated the roles of the cytosolic assembly formed by the Per-Arnt-Sim (PAS) and cyclic nucleotide binding homology (CNBh) domains of the hERG K+ channel in channel gating by using single-chain variable fragment (scFv) antibodies. The authors mapped the scFv2.12 epitope to a site overlapping with the PAS/CNBh domain interface. ScFv binding in vitro and in the cell is incompatible with the PAS interaction with CNBh. Förster resonance energy transfer (FRET) with scFv2.12 can be detected when the channel gate is open but not when it is closed. In addition, state dependence of the scFv2.12 FRET signal disappears when the R56Q mutation, known to destabilize the PAS/CNBh interaction, is introduced in the channel. The authors conclude that the findings are consistent with an extensive structural alteration of the PAS/CNBh assembly when the cytosolic gate opens, likely favoring PAS domain dissociation from the CNBh domain.
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