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

  • 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.
Author:Marina Diskowski, Ahmadreza Mehdipour, Dorith Wunnicke, Deryck J. Mills, Vedrana Mikusevic, Natalie Bärland, Jan Hoffmann, Nina MorgnerORCiDGND, Heinz-Jürgen Steinhoff, Gerhard HummerORCiD, Janet Vonck, Inga Hänelt
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/28504641
Parent Title (English):eLife
Publisher:eLife Sciences Publications
Place of publication:Cambridge
Contributor(s):Kenton J. Swartz
Document Type:Article
Year of Completion:2017
Date of first Publication:2017/05/15
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/01/09
Tag:Biochemistry; Biophysics and structural biology; Cryo-electron microscopy; Ligand-gated ion channel; Md simulations; Membrane transport; Potassium transport; Pulsed epr; Research article
Page Number:21
First Page:1
Last Page:21
Copyright Diskowski et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Institutes:Physik / Physik
Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Angeschlossene und kooperierende Institutionen / MPI für Biophysik
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0