Title | Structural basis for ion selectivity in TMEM175 K channels. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Brunner, J. D., R. P. Jakob, T. Schulze, Y. Neldner, A. Moroni, G. Thiel, T. Maier, and S. Schenck |
Journal | Elife |
Volume | 9 |
Date Published | 2020 Apr 08 |
ISSN | 2050-084X |
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. |
DOI | 10.7554/eLife.53683 |
Alternate Journal | Elife |
PubMed ID | 32267231 |
Grant List | Advanced Grant 495 (AdG) n. 695078 noMAGIC / / H2020 European Research Council / |
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