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| Title | Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel. |
|---|---|
| Journal, issue, pages | Mol Cell, Vol. 83, Issue 14, Page 2524-22539.e7, Year 2023 |
| Publish date | Jul 20, 2023 |
 Authors | Jiyuan Zhang / Weizhong Zeng / Yan Han / Wan-Ru Lee / Jen Liou / Youxing Jiang /  |
| PubMed Abstract | Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key ...Maintaining a highly acidic lysosomal pH is central to cellular physiology. Here, we use functional proteomics, single-particle cryo-EM, electrophysiology, and in vivo imaging to unravel a key biological function of human lysosome-associated membrane proteins (LAMP-1 and LAMP-2) in regulating lysosomal pH homeostasis. Despite being widely used as a lysosomal marker, the physiological functions of the LAMP proteins have long been overlooked. We show that LAMP-1 and LAMP-2 directly interact with and inhibit the activity of the lysosomal cation channel TMEM175, a key player in lysosomal pH homeostasis implicated in Parkinson's disease. This LAMP inhibition mitigates the proton conduction of TMEM175 and facilitates lysosomal acidification to a lower pH environment crucial for optimal hydrolase activity. Disrupting the LAMP-TMEM175 interaction alkalinizes the lysosomal pH and compromises the lysosomal hydrolytic function. In light of the ever-increasing importance of lysosomes to cellular physiology and diseases, our data have widespread implications for lysosomal biology. |
 External links | Mol Cell / PubMed:37390818 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.4 - 3.5 Å |
| Structure data | EMDB-29553, PDB-8fy5: EMDB-29572, PDB-8fyf: |
| Source |
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 Keywords |  MEMBRANE PROTEIN / Complex |
