Structural basis for ion selectivity in TMEM175 K channels.

TitleStructural basis for ion selectivity in TMEM175 K channels.
Publication TypeJournal Article
Year of Publication2020
AuthorsBrunner, J. D., R. P. Jakob, T. Schulze, Y. Neldner, A. Moroni, G. Thiel, T. Maier, and S. Schenck
JournalElife
Volume9
Date Published2020 Apr 08
ISSN2050-084X
Abstract

The TMEM175 family constitutes recently discovered K channels that are important for autophagosome turnover and lysosomal pH regulation and are associated with the early onset of Parkinson Disease. TMEM175 channels lack a P-loop selectivity filter, a hallmark of all known K channels, raising the question how selectivity is achieved. Here, we report the X-ray structure of a closed bacterial TMEM175 channel in complex with a nanobody fusion-protein disclosing bound K ions. Our analysis revealed that a highly conserved layer of threonine residues in the pore conveys a basal K selectivity. An additional layer comprising two serines in human TMEM175 increases selectivity further and renders this channel sensitive to 4-aminopyridine and Zn. Our findings suggest that large hydrophobic side chains occlude the pore, forming a physical gate, and that channel opening by iris-like motions simultaneously relocates the gate and exposes the otherwise concealed selectivity filter to the pore lumen.

DOI10.7554/eLife.53683
Alternate JournalElife
PubMed ID32267231
Grant ListAdvanced Grant 495 (AdG) n. 695078 noMAGIC / / H2020 European Research Council /
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