9DNX

Human ClC-3:TMEM9, TMEM9 Protomer A and B: Complete

This is a non-PDB format compatible entry.

Summary for 9DNX

• Entry DOI: 10.2210/pdb9dnx/pdb
• EMDB information: 47067
• Descriptor: H(+)/Cl(-) exchange transporter 3, Proton-transporting V-type ATPase complex assembly regulator TMEM9, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: ion channel, membrane protein, lysosomal protein, clc
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 227090.43

Authors

Son, Y.,Schrecker, M.,Hite, R.K. (deposition date: 2024-09-18, release date: 2025-04-02)

Primary citation

Schrecker, M.,Son, Y.,Planells-Cases, R.,Kar, S.,Vorobeva, V.,Schulte, U.,Fakler, B.,Jentsch, T.J.,Hite, R.K.
Structural basis of ClC-3 inhibition by TMEM9 and PI(3,5)P 2.
Biorxiv, 2025

PubMed Abstract: The trafficking and activity of endosomes relies on the exchange of chloride ions and protons by members of the CLC family of chloride channels and transporters, whose mutations are associated with numerous diseases. Despite their critical roles, the mechanisms by which CLC transporters are regulated are poorly understood. Here, we show that two related accessory β-subunits, TMEM9 and TMEM9B, directly interact with ClC-3, -4 and -5. Cryo-EM structures reveal that TMEM9 inhibits ClC-3 by sealing the cytosolic entrance to the Cl ion pathway. Unexpectedly, we find that PI(3,5)P stabilizes the interaction between TMEM9 and ClC-3 and is required for proper regulation of ClC-3 by TMEM9. Collectively, our findings reveal that TMEM9 and PI(3,5)P collaborate to regulate endosomal ion homeostasis by modulating the activity of ClC-3.

PubMed: 40093093
DOI: 10.1101/2025.02.28.640562

Experimental method

ELECTRON MICROSCOPY (2.86 Å)