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Structural basis for ion selectivity in TMEM175 K+ channels.


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.

SUBMITTER: Brunner JD 

PROVIDER: S-EPMC7176437 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Structural basis for ion selectivity in TMEM175 K<sup>+</sup> channels.

Brunner Janine D JD   Jakob Roman P RP   Schulze Tobias T   Neldner Yvonne Y   Moroni Anna A   Thiel Gerhard G   Maier Timm T   Schenck Stephan S  

eLife 20200408


The TMEM175 family constitutes recently discovered K<sup>+</sup>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<sup>+</sup> 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<sup>+</  ...[more]

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