A heme-binding domain controls regulation of ATP-dependent potassium channels

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 14; pp. 3785 - 3790
• Main Authors: Burton, Mark J., Kapetanaki, Sofia M., Chernova, Tatyana, Jamieson, Andrew G., Dorlet, Pierre, Santolini, Jérôme, Moody, Peter C. E., Mitcheson, John S., Davies, Noel W., Schmid, Ralf, Raven, Emma L., Storey, Nina M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.04.2016; National Acad Sciences
• Subjects: Adenosine triphosphatase; Amino Acid Motifs - genetics; Animals; Biological Sciences; Cell Line; Chemical compounds; HEK293 Cells; Heme - metabolism; Humans; Iron; KATP Channels - genetics; KATP Channels - metabolism; Life Sciences; Ligands; Mutagenesis; Myocardium - metabolism; Physical Sciences; Potassium; Protein Binding - genetics; Protein Structure, Tertiary; Rats; Rats, Wistar; Sulfonylurea Receptors - chemistry; Sulfonylurea Receptors - genetics; potassium channel; KATP channel; heme; heme regulation; SUR2A
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1600211113

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.