Backup mandate Research Council (Marusa Prolic Kalinsek): Towards a fully open structure of human TMEM175, a lysosomal K + channel and highly relevant drug target in Parkinson`s Disease

Project Details

Description

Parkinson's disease (PD) is a progressive neurodegenerative disorder that primarily affects dopaminergic neurons in the brain. Evidence supports that the accumulation of toxic protein aggregates that occur in PD is caused by dysfunctions in degradation pathways via autophagy and lysosomes. Recently a non-canonical K+ channel of the previously uncharacterized transmembrane protein family 175 (TMEM175) was shown to be critical for lysosomal pH maintenance and autophagosome turnover. Further, numerous genome wide screens revealed a prominent role for TMEM175 in the early onset of PD. Although the precise role of TMEM175 is still investigated it appears that the progression of PD in TMEM175 deficient conditions stems from increased pH in lysosomes (decreased enzyme activity) and the impaired autophagosome clearance. Structures of TMEM175 channels have been reported, but the structure of a fully conductive state is yet to be determined. A naturally occurring variant with higher open probability (Q65P) protects from PD, highlighting that an open channel structure is highly desired for structure-based drug design. Using a combination of cryo-EM and functional in vivo assays we will determine structures of an open-state conformation of the human TMEM175 channel, the protective Q65P variant and of the PD- promoting M393T variant for a deep understanding of the gating mechanism and to establish a blueprint for the rational design of
small molecule agonists in the treatment of PD.
AcronymOZR3966
StatusFinished
Effective start/end date1/11/2230/09/23

Keywords

  • POTTASIUM ION CHANNEL
  • lyosome
  • Parkinson's disease

Flemish discipline codes in use since 2023

  • Structural biology

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