Journal Article

Structural basis for ion selectivity in TMEM175 K+ channels

Schenck, Stephan, Moroni, Anna, Jakob, Roman P, Maier, Timm, Neldner, Yvonne, Thiel, Gerhard, Schulze, Tobias, Brunner, Janine D

2020

Overview

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.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: 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