title: Structurally distinct ligands rescue biogenesis defects of the KATP channel complex via a converging mechanism.
abstract: Small molecules that correct protein misfolding and misprocessing defects offer a potential therapy for numerous human diseases. However, mechanisms underlying pharmacological correction of such defects, especially in heteromeric complexes with structurally diverse constituent proteins, are not well understood. Here we investigate how two chemically distinct compounds, glibenclamide and carbamazepine, correct biogenesis defects in ATP-sensitive potassium (KATP) channels composed of sulfonylurea receptor 1 (SUR1) and Kir6.2. We present evidence that despite structural differences, carbamazepine and glibenclamide compete for binding to KATP channels, and both drugs share a binding pocket in SUR1 to exert their effects. Moreover, both compounds engage Kir6.2, in particular the distal N terminus of Kir6.2, which is involved in normal channel biogenesis, for their chaperoning effects on SUR1 mutants. Conversely, both drugs can correct channel biogenesis defects caused by Kir6.2 mutations in a SUR1-dependent manner. Using an unnatural, photocross-linkable amino acid, azidophenylalanine, genetically encoded in Kir6.2, we demonstrate in living cells that both drugs promote interactions between the distal N terminus of Kir6.2 and SUR1. These findings reveal a converging pharmacological chaperoning mechanism wherein glibenclamide and carbamazepine stabilize the heteromeric subunit interface critical for channel biogenesis to overcome defective biogenesis caused by mutations in individual subunits.
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 devarane@ohsu.edu.
authors: Prasanna K
authors: PK
authors: Devaraneni
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Gregory M
authors: GM
authors: Martin
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Erik M
authors: EM
authors: Olson
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239.
authors: Qing
authors: Q
authors: Zhou
authors: From the Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon 97239 shyngs@ohsu.edu.
authors: Show-Ling
authors: SL
authors: Shyng
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D054086:KATP Channels / Q000096:biosynthesis* / Q000378:metabolism; D008024:Ligands
chemical_list: D054086:KATP Channels; D008024:Ligands; D000255:Adenosine Triphosphate
keywords: ATP-binding Cassette Transporter Subfamily C Member 8 (ABCC8); Carbamazepine; Chaperone; Glibenclamide; Pharmacological Chaperone; Potassium Channel; Protein Assembly; Protein Cross-linking; Sulfonylurea Receptor 1; Unnatural Amino Acid
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