Deciphering the structural gating mechanisms of the lysosomal K⁺/H⁺ channel TMEM175

• Applicant: Professor Dr. Thomas Baukrowitz
• Subject Area: Anatomy and Physiology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 573156182

This project focuses on the protein TMEM175, a known risk factor for Parkinson’s disease (PD). TMEM175 is a H⁺ ion channel localized in the lysosomal membrane, where it regulates lysosomal pH, which is critical for efficient protein degradation. Common genetic loss-of-function variants of TMEM175 (e.g., M393T) are associated with PD, likely because they cause lysosomal over-acidification, impairing protein degradation and promoting the accumulation of toxic proteins such as α-synuclein in the brain. Notably, a common gain-of-function variant (Q65P) appears to protect against PD, suggesting that pharmacological activation of TMEM175 may offer a novel therapeutic strategy. However, the structural mechanisms underlying TMEM175 activation by physiological stimuli and pharmacological compounds remain poorly understood. A key physiological stimulus is the acidic pH of the lysosomal lumen. We aim to identify the pH-sensing amino acids in TMEM175 and elucidate the structural mechanism by which the channel opens to conduct H⁺ ions. Additionally, we aim to identify binding sites for known small-molecule activators of TMEM175 and to screen for novel activators. The recently determined cryo-electron microscopy structure of TMEM175 provides a foundation for structure-guided mutagenesis, which we will use to pinpoint pH-sensing residues, small-molecule binding sites, and key structural elements driving channel activation. Furthermore, we will investigate how common human TMEM175 variants alter channel function. A deeper structural understanding of TMEM175 gating could enable the development of drugs that fine-tune lysosomal pH and thereby slow the progression of Parkinson’s disease.

• DFG Programme: Research Grants