Structural basis for ion selectivity in TMEM175 K + channels

• Published in: eLife 2020-04, Vol.9
• Main Authors: Brunner, Janine D, Jakob, Roman P, Schulze, Tobias, Neldner, Yvonne, Moroni, Anna, Thiel, Gerhard, Maier, Timm, Schenck, Stephan
• Format: Article
• Language: English
• Subjects: Binding sites; Channel opening; Fusion protein; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; ion channel; Ion Channel Gating; macrobody; Models, Molecular; Movement disorders; Nanobodies; nanobody; Neurodegenerative diseases; parkinson disease; Parkinson's disease; Potassium; Potassium - chemistry; Potassium - metabolism; potassium channel; Potassium Channels - chemistry; Potassium Channels - metabolism; Protein Conformation; Proteins; selectivity filter; Serine - chemistry; Serine - metabolism; Structural Biology and Molecular Biophysics; Threonine; Threonine - chemistry; Threonine - metabolism; Vertebrates; Zinc
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.53683

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.