Gating and selectivity mechanisms for the lysosomal K+channel TMEM175
- Memorial Sloan Kettering Cancer Center, United States
Abstract
Transmembrane protein 175 (TMEM175) is a K+-selective ion channel expressed in lysosomal membranes, where it establishes a membrane potential essential for lysosomal function and its dysregulation is associated with the development of Parkinson's Disease. TMEM175 is evolutionarily distinct from all known channels, predicting novel ion-selectivity and gating mechanisms. Here we present cryo-EM structures of human TMEM175 in open and closed conformations, enabled by resolutions up to 2.6Å. Human TMEM175 adopts a homodimeric architecture with a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, these same residues establish a constriction essential for K+ selectivity. These studies reveal the mechanisms of permeation, selectivity and gating and lay the groundwork for understanding the role of TMEM175 in lysosomal function.
Data availability
Cryo-EM maps and atomic coordinates have been deposited with the EMDB and PDB under accession codes EMDB-21603 and PDB 6WC9 for Class 1 TMEM175 in K+, codes EMDB-21604 and PDB 6WCA for Class 2 TMEM175 in K+, codes EMDB-21605 and PDB 6WCB Class 1 TMEM175 in Cs+ and codes EMDB-21606 and PDB 6WCC for Class 2 TMEM175 in Cs+ All other reagents are available from the corresponding author upon reasonable request.
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Cryo-EM structure of human TMEM175 in an open state in K+Protein Data Bank, 6WC9.
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Cryo-EM structure of human TMEM175 in an closed state in K+Protein Data Bank, 6WCA.
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Cryo-EM structure of human TMEM175 in an open state in Cs+Protein Data Bank, 6WCB.
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Cryo-EM structure of human TMEM175 in an closed state in Cs+Protein Data Bank, 6WCC.
Article and author information
Author details
Funding
Searle Scholars Program
- Richard K Hite
Josie Robertson Investigators Program
- Richard K Hite
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Oh et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Gating and selectivity mechanisms for the lysosomal K+channel TMEM175
eLife 9:e53430.
https://doi.org/10.7554/eLife.53430
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