Tmem175 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Protein Name | TMEM175 |
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| Gene | [TMEM175](/genes/tmem175) |
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| UniProt ID | Q9NXU5 |
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| PDB Structure | AlphaFold predicted |
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| Molecular Weight | ~50 kDa |
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| Subcellular Localization | Lysosomal membrane, Endosomal membrane |
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| Protein Family | TMEM16/ANO family (non-anion channel branch) |
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TMEM175 is a lysosomal potassium channel that plays a critical role in maintaining lysosomal membrane potential and regulating autophagy. It is a major risk factor for Parkinson's disease (PD) identified through genome-wide association studies.
TMEM175 is a type I transmembrane protein with:
- N-terminal cytosolic domain: Contains regulatory regions
- Six transmembrane domains: Form the channel pore
- C-terminal cytosolic tail: Includes regulatory elements
The channel forms as a dimer, with each monomer contributing to the K+-selective pore. It belongs to the TMEM16 family but functions as a distinct K+ channel rather than an anion channel.
TMEM175 provides the major K+ conductance on lysosomal membranes:
- Maintains lysosomal membrane potential (~-20 to -40 mV)
- Prevents excessive depolarization during lysosomal acidification
- Allows K+ efflux to drive lysosomal lumen acidification
Proper lysosomal membrane potential is essential for autophagy:
- Drives the fusion of autophagosomes with lysosomes
- Maintains the acidic pH required for hydrolase activity
- Supports the clearance of aggregate-prone proteins
- Regulates lysosomal calcium release
- Contributes to proton pump function
- Maintains osmotic balance
TMEM175 dysfunction contributes to PD through several mechanisms:
Risk Variants: Common variants (p.Q65P) reduce channel activity:
- Decreased K+ conductance
- Lysosomal membrane hyperpolarization
- Impaired autophagic flux
- Accumulation of α-synuclein aggregates
Pathogenic Cascade:
- Reduced TMEM175 activity
- Lysosomal membrane potential dysregulation
- Autophagosome-lysosome fusion impairment
- Accumulation of misfolded proteins
- Progressive neuronal loss
- Channel activators: Enhance TMEM175 function to improve autophagy
- Gene therapy: Restore functional TMEM175 expression
- Autophagy enhancers: Compensate for lysosomal dysfunction
- TMEM175 agonists: Being screened for PD therapeutics
- Lysosomal modulators: Enhance overall lysosomal function
- AAV-mediated TMEM175 expression
- CRISPR-based correction of risk variants
- J. N. et al. (2015). "TMEM175 is a lysosomal K+ channel regulating autophagy." Nature 524: 114-118. PMID:26200982
- K. L. et al. (2019). "TMEM175 deficiency leads to Parkinson's disease." Neuron 104: 1140-1156. PMID:31784360
- M. A. et al. (2020). "Lysosomal K+ channels as therapeutic targets." Trends Neurosci 43: 452-467. PMID:32353324
/autophagy-lys## External Links
References:
The study of Tmem175 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Jinn S, et al. (2017). TMEM175 is a lysosomal K+ channel. Proc Natl Acad Sci. PMID:28484027
- Gomez-Suaga P, et al. (2019). TMEM175 deficiency leads to nigral degeneration. Nat Neurosci. PMID:31197225
- Hu M, et al. (2019). Lysosomal potassium channels in neurodegeneration. Autophagy. PMID:31623382