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Structural basis for ion selectivity in TMEM175 K+ channels


Brunner, Janine D; Jakob, Roman P; Schulze, Tobias; Neldner, Yvonne; Moroni, Anna; Thiel, Gerhard; Maier, Timm; Schenck, Stephan (2020). Structural basis for ion selectivity in TMEM175 K+ channels. eLife, 9:Epub ahead of print.

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 Zn2+. 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.

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 Zn2+. 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Department of Trauma Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > General Immunology and Microbiology
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Language:English
Date:8 April 2020
Deposited On:16 Apr 2020 07:00
Last Modified:20 May 2020 20:48
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/eLife.53683
PubMed ID:32267231

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