title: A heme-binding domain controls regulation of ATP-dependent potassium channels.
abstract: Heme iron has many and varied roles in biology. Most commonly it binds as a prosthetic group to proteins, and it has been widely supposed and amply demonstrated that subtle variations in the protein structure around the heme, including the heme ligands, are used to control the reactivity of the metal ion. However, the role of heme in biology now appears to also include a regulatory responsibility in the cell; this includes regulation of ion channel function. In this work, we show that cardiac KATP channels are regulated by heme. We identify a cytoplasmic heme-binding CXXHX16H motif on the sulphonylurea receptor subunit of the channel, and mutagenesis together with quantitative and spectroscopic analyses of heme-binding and single channel experiments identified Cys628 and His648 as important for heme binding. We discuss the wider implications of these findings and we use the information to present hypotheses for mechanisms of heme-dependent regulation across other ion channels.
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom;
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Burton
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom;
authors.forename: Sofia M
authors.initials: SM
authors.lastname: Kapetanaki
authors.affiliation: MRC Toxicology Unit, Leicester LE1 9HN, United Kingdom;
authors.forename: Tatyana
authors.initials: T
authors.lastname: Chernova
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom;
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Jamieson
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette cedex, France;
authors.forename: Pierre
authors.initials: P
authors.lastname: Dorlet
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, 91198, Gif-sur-Yvette cedex, France;
authors.forename: Jérôme
authors.initials: J
authors.lastname: Santolini
authors.affiliation: Department of Molecular and Cell Biology and Henry Wellcome Laboratories for Structural Biology, University of Leicester, Leicester LE1 9HN, United Kingdom.
authors.forename: Peter C E
authors.identifier: http://orcid.org/0000-0003-1762-9238
authors.initials: PC
authors.lastname: Moody
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom;
authors.forename: John S
authors.initials: JS
authors.lastname: Mitcheson
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom;
authors.forename: Noel W
authors.initials: NW
authors.lastname: Davies
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom;
authors.forename: Ralf
authors.initials: R
authors.lastname: Schmid
authors.affiliation: Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom; emma.raven@le.ac.uk ns140@le.ac.uk.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Raven
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester LE1 9HN, United Kingdom; emma.raven@le.ac.uk ns140@le.ac.uk.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Storey
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D002460:Cell Line; D057809:HEK293 Cells; D006418:Heme / Q000378:metabolism*; D006801:Humans; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D064233:Sulfonylurea Receptors / Q000737:chemistry* / Q000235:genetics
chemical_list: D054086:KATP Channels; D064233:Sulfonylurea Receptors; D006418:Heme
keywords: KATP channel; SUR2A; heme; heme regulation; potassium channel