title: DEND mutation in Kir6.2 (KCNJ11) reveals a flexible N-terminal region critical for ATP-sensing of the KATP channel.
abstract: ATP-sensitive K(+)-channels link metabolism and excitability in neurons, myocytes, and pancreatic islets. Mutations in the pore-forming subunit (Kir6.2; KCNJ11) cause neonatal diabetes, developmental delay, and epilepsy by decreasing sensitivity to ATP inhibition and suppressing electrical activity. Mutations of residue G53 underlie both mild (G53R,S) and severe (G53D) forms of the disease. All examined substitutions (G53D,R,S,A,C,F) reduced ATP-sensitivity, indicating an intolerance of any amino acid other than glycine. Surprisingly, each mutation reduces ATP affinity, rather than intrinsic gating, although structural modeling places G53 at a significant distance from the ATP-binding pocket. We propose that glycine is required in this location for flexibility of the distal N-terminus, and for an induced fit of ATP at the binding site. Consistent with this hypothesis, glycine substitution of the adjacent residue (Q52G) partially rescues ATP affinity of reconstituted Q52G/G53D channels. The results reveal an important feature of the noncanonical ATP-sensing mechanism of K(ATP) channels.
authors: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Joseph C
authors: JC
authors: Koster
authors: Harley T
authors: HT
authors: Kurata
authors: Decha
authors: D
authors: Enkvetchakul
authors: Colin G
authors: CG
authors: Nichols
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D054086:KATP Channels / Q000737:chemistry / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel