Differential ion dehydration energetics explains selectivity in the non-canonical lysosomal K+ channel TMEM175. Elife 2022 May 24;11
Date
05/25/2022Pubmed ID
35608336Pubmed Central ID
PMC9129878DOI
10.7554/eLife.75122Scopus ID
2-s2.0-85130675029 (requires institutional sign-in at Scopus site) 21 CitationsAbstract
Structures of the human lysosomal K+ channel transmembrane protein 175 (TMEM175) in open and closed states revealed a novel architecture lacking the canonical K+ selectivity filter motif present in previously known K+ channel structures. A hydrophobic constriction composed of four isoleucine residues was resolved in the pore and proposed to serve as the gate in the closed state, and to confer ion selectivity in the open state. Here, we achieve higher-resolution structures of the open and closed states and employ molecular dynamics simulations to analyze the conducting properties of the putative open state, demonstrating that it is permeable to K+ and, to a lesser degree, also Na+. Both cations must dehydrate significantly to penetrate the narrow hydrophobic constriction, but ion flow is assisted by a favorable electrostatic field generated by the protein that spans the length of the pore. The balance of these opposing energetic factors explains why permeation is feasible, and why TMEM175 is selective for K+ over Na+, despite the absence of the canonical selectivity filter. Accordingly, mutagenesis experiments reveal an exquisite sensitivity of the channel to perturbations that mitigate the constriction. Together, these data reveal a novel mechanism for selective permeation of ions by TMEM175 that is unlike that of other K+ channels.
Author List
Oh S, Marinelli F, Zhou W, Lee J, Choi HJ, Kim M, Faraldo-Gómez JD, Hite RKAuthor
Fabrizio Marinelli PhD Associate Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
DehydrationHumans
Ions
Lysosomes
Molecular Dynamics Simulation
Potassium
Potassium Channels
Protein Conformation
Sodium
