Discovery of a heme-binding domain in a neuronal voltage-gated potassium channel.

Autor:	Burton MJ; Department of Chemistry, University of Leicester, Leicester, United Kingdom; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom., Cresser-Brown J; School of Chemistry, University of Bristol, Bristol, United Kingdom., Thomas M; Department of Chemistry, University of Leicester, Leicester, United Kingdom; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom., Portolano N; Department of Chemistry, University of Leicester, Leicester, United Kingdom; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom., Basran J; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Freeman SL; School of Chemistry, University of Bristol, Bristol, United Kingdom., Kwon H; School of Chemistry, University of Bristol, Bristol, United Kingdom., Bottrill AR; Protein Nucleic Acid Chemistry Laboratory, University of Leicester, Leicester, United Kingdom., Llansola-Portoles MJ; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell, Gif-sur-Yvette, France., Pascal AA; Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell, Gif-sur-Yvette, France., Jukes-Jones R; Medical Research Council Toxicology Unit, University of Cambridge, Leicester, United Kingdom., Chernova T; Medical Research Council Toxicology Unit, University of Cambridge, Leicester, United Kingdom., Schmid R; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Davies NW; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Storey NM; Leicester Institute of Structural and Chemical Biology, University of Leicester, Leicester, United Kingdom; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Dorlet P; CNRS, Aix Marseille Université, Laboratoire de Bioenergetique et d'Ingenierie des Protéines, Marseille, France., Moody PCE; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Mitcheson JS; Department of Molecular and Cell Biology, University of Leicester, Leicester, United Kingdom., Raven EL; School of Chemistry, University of Bristol, Bristol, United Kingdom. Electronic address: emma.raven@bristol.ac.uk.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2020 Sep 18; Vol. 295 (38), pp. 13277-13286. Date of Electronic Publication: 2020 Jul 28.
DOI:	10.1074/jbc.RA120.014150
Abstrakt:	The EAG ( ether-à-go-go ) family of voltage-gated K + channels are important regulators of neuronal and cardiac action potential firing (excitability) and have major roles in human diseases such as epilepsy, schizophrenia, cancer, and sudden cardiac death. A defining feature of EAG (Kv10-12) channels is a highly conserved domain on the N terminus, known as the eag domain, consisting of a Per-ARNT-Sim (PAS) domain capped by a short sequence containing an amphipathic helix (Cap domain). The PAS and Cap domains are both vital for the normal function of EAG channels. Using heme-affinity pulldown assays and proteomics of lysates from primary cortical neurons, we identified that an EAG channel, hERG3 (Kv11.3), binds to heme. In whole-cell electrophysiology experiments, we identified that heme inhibits hERG3 channel activity. In addition, we expressed the Cap and PAS domain of hERG3 in Escherichia coli and, using spectroscopy and kinetics, identified the PAS domain as the location for heme binding. The results identify heme as a regulator of hERG3 channel activity. These observations are discussed in the context of the emerging role for heme as a regulator of ion channel activity in cells. Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article. (© 2020 Burton et al.)
Databáze:	MEDLINE
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