Helical jackknives control the gates of the double-pore K+ uptake system KtrAB

ELife
Marina DiskowskiInga Hänelt

Abstract

Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukaryotic and most bacterial ligand-gated K+ channels, RCK domains regulate ion fluxes. Until now, a single regulatory mechanism has been proposed for all RCK-regulated channels, involving signal transduction from the RCK domain to the gating area. Here, we present an inactive ADP-bound structure of KtrAB from Vibrio alginolyticus, determined by cryo-electron microscopy, which, combined with EPR spectroscopy and molecular dynamics simulations, uncovers a novel regulatory mechanism for ligand-induced action at a distance. Exchange of activating ATP to inactivating ADP triggers short helical segments in the K+-translocating KtrB dimer to organize into two long helices that penetrate deeply into the regulatory RCK domains, thus connecting nucleotide-binding sites and ion gates. As KtrAB and its homolog TrkAH have been implicated as bacterial pathogenicity factors, the discovery of this functionally relevant inactive conformation may advance structure-guided drug development.

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Citations

Aug 6, 2019·Chembiochem : a European Journal of Chemical Biology·Hendrik R SikkemaBert Poolman
Jul 13, 2019·Scientific Reports·Masaru TsujiiNobuyuki Uozumi
Jul 31, 2019·Biological Chemistry·Marina SchreckerInga Hänelt
Oct 19, 2019·The Journal of General Physiology·Vedrana MikuševićInga Hänelt
Nov 20, 2018·Chemical Communications : Chem Comm·Nils HellwigNina Morgner
Nov 30, 2019·Nucleic Acids Research·Marcel HeinzGerhard Hummer
Jul 2, 2019·Molecular Membrane Biology·Bjørn P PedersenHans-Jürgen Apell
Mar 19, 2021·Frontiers in Microbiology·Andreia S FernandesCarol A Harley
Apr 3, 2021·Journal of Molecular Biology·Janina StautzInga Hänelt
May 22, 2018·Journal of Chemical Information and Modeling·Yu-Jiao YangHong-Bin Shen
Sep 14, 2018·The Journal of Physical Chemistry Letters·Katrin ReichelGerhard Hummer

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Methods Mentioned

BETA
electron paramagnetic resonance
X-ray
size-exclusion chromatography

Software Mentioned

ABDGB
CD
TM
BLAST
Situs
Modeller
DeerAnalysis
VMD1
MDFF
GeneDoc

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