Department of Biochemistry, University of Zürich, Zürich, Switzerland; Department Biozentrum, University of Basel, Basel, Switzerland; Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland; VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
Roman P Jakob
Department Biozentrum, University of Basel, Basel, Switzerland
Tobias Schulze
Membrane Biophysics, Technical University of Darmstadt, Darmstadt, Germany
Yvonne Neldner
Department of Biochemistry, University of Zürich, Zürich, Switzerland
Department Biozentrum, University of Basel, Basel, Switzerland
Stephan Schenck
Department of Biochemistry, University of Zürich, Zürich, Switzerland; Laboratory of Biomolecular Research, Paul Scherrer Institut, Villigen, Switzerland; VIB-VUB Center for Structural Biology, VIB, Brussels, Belgium; Structural Biology Brussels, Vrije Universiteit Brussel, Brussels, Belgium
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.
