7LF6

Structure of lysosomal membrane protein

Summary for 7LF6

• Entry DOI: 10.2210/pdb7lf6/pdb
• Related: 6W8N 6W8P
• EMDB information: 23300
• Descriptor: Endosomal/lysosomal potassium channel TMEM175 (1 entity in total)
• Functional Keywords: channel, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 111334.44

Authors

Shen, C.,Fu, T.M.,Wang, L.F.,Rawson, S.,Wu, H. (deposition date: 2021-01-15, release date: 2022-01-26, Last modification date: 2024-11-13)

Primary citation

Zheng, W.,Shen, C.,Wang, L.,Rawson, S.,Xie, W.J.,Nist-Lund, C.,Wu, J.,Shen, Z.,Xia, S.,Holt, J.R.,Wu, H.,Fu, T.M.
pH regulates potassium conductance and drives a constitutive proton current in human TMEM175.
Sci Adv, 8:eabm1568-eabm1568, 2022

PubMed Abstract: Human TMEM175, a noncanonical potassium (K) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson's disease (PD). Structurally, the TMEM175 family exhibits an architecture distinct from canonical potassium channels, as it lacks the typical TVGYG selectivity filter. Here, we show that human TMEM175 not only exhibits pH-dependent structural changes that reduce K permeation at acidic pH but also displays proton permeation. TMEM175 constitutively conducts K at pH 7.4 but displays reduced K permeation at lower pH. In contrast, proton current through TMEM175 increases with decreasing pH because of the increased proton gradient. Molecular dynamics simulation, structure-based mutagenesis, and electrophysiological analysis suggest that K ions and protons share the same permeation pathway. The M393T variant of human TMEM175 associated with PD shows reduced function in both K and proton permeation. Together, our structural and electrophysiological analysis reveals a mechanism of TMEM175 regulation by pH.

PubMed: 35333573
DOI: 10.1126/sciadv.abm1568

Experimental method

ELECTRON MICROSCOPY (3.5 Å)