9GI8

Solution structure of homodimeric TMEM106B

Summary for 9GI8

• Entry DOI: 10.2210/pdb9gi8/pdb
• Related: 8AMS
• NMR Information: BMRB: 34953
• Descriptor: Transmembrane protein 106B, ZINC ION (2 entities in total)
• Functional Keywords: zinc-binding, lysosomal, n-terminal cytoplasmic domain, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 8759.23

Authors

Schweimer, K.,Perez-Borrajero, C.,Hennig, J. (deposition date: 2024-08-17, release date: 2025-11-26, Last modification date: 2026-06-10)

Primary citation

Perez-Borrajero, C.,Stein, F.,Schweimer, K.,Rettel, M.,Schwarz, J.J.,Haberkant, P.,Lapouge, K.,Gayk, J.,Hoffmann, T.,Bhogaraju, S.,Noh, K.M.,Savitski, M.,Mahamid, J.,Hennig, J.
TRIM2 E3 ligase substrate discovery reveals zinc-mediated regulation of TMEM106B in the endolysosomal pathway.
Embo Rep., 27:729-747, 2026

PubMed Abstract: TRIM2 is a mammalian E3 ligase with particularly high expression in Purkinje neurons, where it contributes to neuronal development and homeostasis. The understanding of ubiquitin E3 ligase function hinges on thoroughly identifying their cellular targets, but the transient nature of signaling complexes leading to ubiquitination poses a significant challenge for detailed mechanistic studies. Here, we tailored a recently developed ubiquitin-specific proximity labeling tool to identify substrates of TRIM2 in cells. We show that TRIM2 targets proteins involved in the endolysosomal pathway. Specifically, we demonstrate using biochemical and structural studies, that TRIM2 ubiquitinates TMEM106B at lysine residues located in the cytosolic N-terminal region. Substrate recognition involves a direct interaction between TRIM2 and a newly identified zinc-coordination motif in TMEM106B that mediates homodimerization, is required for specific protein-protein interactions, and lysosomal size regulation. We found that in addition to catalysis, the tripartite motif is involved in substrate recruitment. Our study thus contributes a catalog of TRIM2 effectors and identifies a previously unrecognized regulatory region of TMEM106B crucial to its function.

PubMed: 41484378
DOI: 10.1038/s44319-025-00667-3

Experimental method

SOLUTION NMR