8FY5

Human TMEM175-LAMP1 full-length complex

Summary for 8FY5

• Entry DOI: 10.2210/pdb8fy5/pdb
• EMDB information: 29553
• Descriptor: Endosomal/lysosomal potassium channel TMEM175, Lysosome-associated membrane glycoprotein 1 (2 entities in total)
• Functional Keywords: complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 201190.87

Authors

Zhang, J.Y.,Zeng, W.Z.,Han, Y.,Jiang, Y.X. (deposition date: 2023-01-25, release date: 2023-06-28, Last modification date: 2024-06-19)

Primary citation

Zhang, J.,Zeng, W.,Han, Y.,Lee, W.R.,Liou, J.,Jiang, Y.
Lysosomal LAMP proteins regulate lysosomal pH by direct inhibition of the TMEM175 channel.
Mol.Cell, 83:2524-2539.e7, 2023

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 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.

PubMed: 37390818
DOI: 10.1016/j.molcel.2023.06.004

Experimental method

ELECTRON MICROSCOPY (3.5 Å)