Parkinson's risk factor TMEM175 is a pH-gated proton and potassium channel

What is it about?

TMEM175 is a lysosomal ion channel whose biophysical properties and cellular function are poorly understood. Previous studies have reported conflicting results regarding ion selectivity and gating. In our work, we show that TMEM175 conducts protons and potassium ions in both the lysosomal and the plasma membrane, with the permeability for protons exceeding that for potassium ions by a factor of approximately 50,000 at a luminal pH of 4.7. In patch-clamp experiments, the high proton conductance of TMEM175 causes the rapid collapse of the pH-gradient across the membrane. Moreover, we can show that TMEM175 is gated by acidification of the luminal side. TMEM175 is therefore a proton-activated proton and potassium channel. Histidine 57 on the luminal side of the protein acts as a pH sensor: acidification of the lysosomal lumen leads to protonation of His57, which then interacts with negatively charged amino acid residues at the luminal pore entrance and stabilizes the open state of the channel by forming a salt bridge network.

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Photo by ANIRUDH on Unsplash

Photo by ANIRUDH on Unsplash

Why is it important?

Lysosomes must maintain an internal acidic pH in the range of 4.5–5.0 in order to perform their cellular functions. Acidification is achieved by a V-ATPase, which pumps protons from the cytosol into the lysosomal lumen using ATP. As a pH-regulated proton and potassium channel, TMEM175 is likely to be directly involved in balancing lysosomal pH. Disruption of this regulatory mechanism, for example through mutations in TMEM175, can lead to disturbances in cellular degradation and signaling processes and, in the worst case, to disorders such as Parkinson's disease. Our findings on the biophysical properties of TMEM175 allow us to better understand the role of TMEM175 in lysosome function under physiological and pathophysiological conditions.