title: The Caenorhabditis elegans iodotyrosine deiodinase ortholog SUP-18 functions through a conserved channel SC-box to regulate the muscle two-pore domain potassium channel SUP-9.
abstract: Loss-of-function mutations in the Caenorhabditis elegans gene sup-18 suppress the defects in muscle contraction conferred by a gain-of-function mutation in SUP-10, a presumptive regulatory subunit of the SUP-9 two-pore domain K(+) channel associated with muscle membranes. We cloned sup-18 and found that it encodes the C. elegans ortholog of mammalian iodotyrosine deiodinase (IYD), an NADH oxidase/flavin reductase that functions in iodine recycling and is important for the biosynthesis of thyroid hormones that regulate metabolism. The FMN-binding site of mammalian IYD is conserved in SUP-18, which appears to require catalytic activity to function. Genetic analyses suggest that SUP-10 can function with SUP-18 to activate SUP-9 through a pathway that is independent of the presumptive SUP-9 regulatory subunit UNC-93. We identified a novel evolutionarily conserved serine-cysteine-rich region in the C-terminal cytoplasmic domain of SUP-9 required for its specific activation by SUP-10 and SUP-18 but not by UNC-93. Since two-pore domain K(+) channels regulate the resting membrane potentials of numerous cell types, we suggest that the SUP-18 IYD regulates the activity of the SUP-9 channel using NADH as a coenzyme and thus couples the metabolic state of muscle cells to muscle membrane excitability.
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Ignacio Perez
authors.initials: IP
authors.lastname: de la Cruz
authors.affiliation: State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Long
authors.initials: L
authors.lastname: Ma
authors.affiliation: Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: H Robert
authors.initials: HR
authors.lastname: Horvitz
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics* / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D015221:Potassium Channels; C478296:Sup-10 protein, C elegans; C478295:Sup-9 protein, C elegans; D007453:Iodide Peroxidase