Structural basis for ion selectivity in TMEM175 K+ channels

Abstract
Data availability
Article and author information
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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.

Data availability

Atomic coordinates have been deposited at the Protein Data Bank with thefollowing unique identifiers: 6HD8, 6HD9, 6HDA, 6HDB, 6HDC, 6SWR.

The following data sets were generated

1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2019) Crystal structure of the potassium channel MtTMEM175 in complex with a Nanobody-MBP fusion protein
Protein Data Bank, 6HD8.

https://www.rcsb.org/structure/6HD8
1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2019) Crystal structure of the potassium channel MtTMEM175 with rubidium
Protein Data Bank, 6HD9.

https://www.rcsb.org/structure/6HD9
1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2019) Crystal structure of the potassium channel MtTMEM175 with cesium
Protein Data Bank, 6HDA.

https://www.rcsb.org/structure/6HDA
1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2019) Crystal structure of the potassium channel MtTMEM175 with zinc
Protein Data Bank, 6HDB.

https://www.rcsb.org/structure/6HDB
1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2019) Crystal structure of the potassium channel MtTMEM175 T38A variant in complex with a Nanobody-MBP fusion protein
Protein Data Bank, 6HDC.

https://www.rcsb.org/structure/6HDC
1. Brunner JD
2. Jakob RP
3. Schulze T
4. Neldner Y
5. Moroni A
6. Thiel G
7. Maier T
8. Schenck S
(2020) Atomic coordinates
Protein Data Bank, 6SWR.

https://www.rcsb.org/structure/6SWR

The following previously published data sets were used

1. Lee C
2. Guo J
3. Jiang Y
(2017) Crystal structure of a lysosomal potassium-selective channel TMEM175 homolog from Chamaesiphon Minutus
Protein Data Bank, 5VRE.

https://www.rcsb.org/structure/5VRE

Article and author information

Author details

Janine D Brunner

VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium

For correspondence
janine.brunner@vub.be

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-4237-9322
Roman P Jakob

Biozentrum, University of Basel, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.
Tobias Schulze

Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany

Competing interests
The authors declare that no competing interests exist.
Yvonne Neldner

Department of Trauma, University Hospital Zürich, Zürich, Switzerland

Competing interests
The authors declare that no competing interests exist.
Anna Moroni

Department of Biosciences, University of Milan, Milan, Italy

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-1860-406X
Gerhard Thiel

Department of Biology, Technische Universität Darmstadt, Darmstadt, Germany

Competing interests
The authors declare that no competing interests exist.
Timm Maier

Biozentrum, University of Basel, Basel, Switzerland

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-7459-1363
Stephan Schenck

VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium

For correspondence
stephan.schenck@vub.be

Competing interests
The authors declare that no competing interests exist.

Funding

H2020 European Research Council (Advanced Grant 495 (AdG) n. 695078 noMAGIC)

Anna Moroni
Gerhard Thiel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

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.