8R79

The D2 domain of human DTX3L

Summary for 8R79

• Entry DOI: 10.2210/pdb8r79/pdb
• Descriptor: E3 ubiquitin-protein ligase DTX3L, SULFATE ION (2 entities in total)
• Functional Keywords: ubiquitin ligase, homo 4-mer, n-terminal domain, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 35091.52

Authors

Vela-Rodriguez, C.,Lehtio, L.,Maksimainen, M.,Duman, R.,Wagner, A.,Glumoff, T. (deposition date: 2023-11-24, release date: 2023-12-27, Last modification date: 2025-03-05)

Primary citation

Vela-Rodriguez, C.,Yang, C.,Alanen, H.I.,Eki, R.,Abbas, T.A.,Maksimainen, M.M.,Glumoff, T.,Duman, R.,Wagner, A.,Paschal, B.M.,Lehtio, L.
Oligomerization mediated by the D2 domain of DTX3L is critical for DTX3L-PARP9 reading function of mono-ADP-ribosylated androgen receptor.
Protein Sci., 33:e4945-e4945, 2024

PubMed Abstract: Deltex proteins are a family of E3 ubiquitin ligases that encode C-terminal RING and DTC domains that mediate interactions with E2 ubiquitin-conjugating enzymes and recognize ubiquitination substrates. DTX3L is unique among the Deltex proteins based on its N-terminal domain architecture. The N-terminal D1 and D2 domains of DTX3L mediate homo-oligomerization, and the D3 domain interacts with PARP9, a protein that contains tandem macrodomains with ADP-ribose reader function. While DTX3L and PARP9 are known to heterodimerize, and assemble into a high molecular weight oligomeric complex, the nature of the oligomeric structure, including whether this contributes to the ADP-ribose reader function is unknown. Here, we report a crystal structure of the DTX3L N-terminal D2 domain and show that it forms a tetramer with, conveniently, D2 symmetry. We identified two interfaces in the structure: a major, conserved interface with a surface of 973 Å and a smaller one of 415 Å. Using native mass spectrometry, we observed molecular species that correspond to monomers, dimers and tetramers of the D2 domain. Reconstitution of DTX3L knockout cells with a D1-D2 deletion mutant showed the domain is dispensable for DTX3L-PARP9 heterodimer formation, but necessary to assemble an oligomeric complex with efficient reader function for ADP-ribosylated androgen receptor. Our results suggest that homo-oligomerization of DTX3L is important for the DTX3L-PARP9 complex to read mono-ADP-ribosylation on a ligand-regulated transcription factor.

PubMed: 38511494
DOI: 10.1002/pro.4945

Experimental method

X-RAY DIFFRACTION (2.18 Å)