Activation mechanism of ATP-sensitive K+ channels explored with real-time nucleotide binding.

ELife
Michael C PuljungFrances M Ashcroft

Abstract

The response of ATP-sensitive K+ channels (KATP) to cellular metabolism is coordinated by three classes of nucleotide binding site (NBS). We used a novel approach involving labeling of intact channels in a native, membrane environment with a non-canonical fluorescent amino acid and measurement (using FRET with fluorescent nucleotides) of steady-state and time-resolved nucleotide binding to dissect the role of NBS2 of the accessory SUR1 subunit of KATP in channel gating. Binding to NBS2 was Mg2+-independent, but Mg2+ was required to trigger a conformational change in SUR1. Mutation of a lysine (K1384A) in NBS2 that coordinates bound nucleotides increased the EC50 for trinitrophenyl-ADP binding to NBS2, but only in the presence of Mg2+, indicating that this mutation disrupts the ligand-induced conformational change. Comparison of nucleotide-binding with ionic currents suggests a model in which each nucleotide binding event to NBS2 of SUR1 is independent and promotes KATP activation by the same amount.

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Citations

Jul 28, 2020·The Journal of Physiology·N BraunS A Pless
May 8, 2020·Nature Reviews. Endocrinology·Tanadet PipatpolkaiFrances M Ashcroft
Aug 24, 2019·Research in Microbiology·I Barry Holland
Jun 18, 2021·Journal of Molecular Biology·Tanadet PipatpolkaiPhillip J Stansfeld
Aug 11, 2021·Wellcome Open Research·Gregor SachseFrances M Ashcroft
Aug 13, 2021·Neural Regeneration Research·Iván Alquisiras-BurgosPenélope Aguilera
Jul 2, 2021·Biochemistry·Mia A ShandellVirginia W Cornish
Nov 27, 2021·The Journal of Physical Chemistry. B·Katarzyna Walczewska-Szewc, Wieslaw Nowak

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Methods Mentioned

BETA
FRET
transfection
ELISA

Software Mentioned

PyMOL
LightField
Matlab
Fiji
pClamp
Origin

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