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.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Koster JC,Kurata HT,Enkvetchakul D,Nichols CG

doi

10.1529/biophysj.108.138685

subject

Has Abstract

pub_date

2008-11-15 00:00:00

pages

4689-97

issue

10

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(08)78608-9

journal_volume

95

pub_type

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