Structurally distinct ligands rescue biogenesis defects of the KATP channel complex via a converging mechanism

Prasanna K. Devaraneni, Erik M. Olson, Qing Zhou, Show-Ling Shyng

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7980-7991
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number12
DOIs
StatePublished - Mar 20 2015

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Sulfonylurea Receptors
KATP Channels
Glyburide
Ligands
Carbamazepine
Defects
Drug interactions
Pharmacology
Mutation
Drug Interactions
Pharmaceutical Preparations
Potassium
Proteins
Adenosine Triphosphate
Cells
Amino Acids
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structurally distinct ligands rescue biogenesis defects of the KATP channel complex via a converging mechanism. / Devaraneni, Prasanna K.; Olson, Erik M.; Zhou, Qing; Shyng, Show-Ling.

In: Journal of Biological Chemistry, Vol. 290, No. 12, 20.03.2015, p. 7980-7991.

Research output: Contribution to journalArticle

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