Structural basis for ion selectivity in TMEM175 K+ channels
- Elife. 2020 Apr 8;9:e53683. doi: 10.7554/eLife.53683.
- 1. Department of Biochemistry, University of Zürich, Zürich, Switzerland.
- 2. Department Biozentrum, University of Basel, Basel, Switzerland.
- 3. Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland.
- 4. VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium.
- 5. Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium.
- 6. Membrane Biophysics, Technical University of Darmstadt, Darmstadt, Germany.
- 7. Department of Biosciences, University of Milano, Milan, Italy.
- # Contributed equally.
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.