|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|
|Date Published||2020 Apr 08|
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.
|Grant List||Advanced Grant 495 (AdG) n. 695078 noMAGIC / / H2020 European Research Council /|
Structural basis for ion selectivity in TMEM175 K channels.