title: Engineered Kir6.2 mutations that correct the trafficking defect of K(ATP) channels caused by specific SUR1 mutations.
abstract: KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion. The molecular interactions between SUR1 and Kir6.2 that govern channel gating and biogenesis are incompletely understood. In a recent study, we showed that a SUR1 and Kir6.2 mutation pair, E203K-SUR1 and Q52E-Kir6.2, at the SUR1/Kir6.2 interface near the plasma membrane increases the ATP-sensitivity of the channel by nearly 100-fold. Here, we report the finding that the same mutation pair also suppresses channel folding/trafficking defects caused by select SUR1 mutations in the first transmembrane domain of SUR1. Analysis of the contributions from individual mutations, however, revealed that the correction effect is attributed largely to Q52E-Kir6.2 alone. Moreover, the correction is dependent on the negative charge of the substituting amino acid at the Q52 position in Kir6.2. Our study demonstrates for the first time that engineered mutations in Kir6.2 can correct the biogenesis defect caused by specific mutations in the SUR1 subunit.
authors.affiliation: Department of Biochemistry and Molecular Biology; Oregon Health & Science University; Portland, OR USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Emily B
authors.initials: EB
authors.lastname: Pratt
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D000818:Animals; D006224:Cricetinae; D008958:Models, Molecular; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D064233:Sulfonylurea Receptors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D024661:Potassium Channels, Inwardly Rectifying; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
keywords: KATP channel; Kir6.2; biogenesis; sulfonylurea receptor 1; trafficking