Oligomerization mediated by the D2 domain of DTX3L is critical for DTX3L‐PARP9 reading function of mono‐ADP‐ribosylated androgen receptor

Author:

Vela‐Rodríguez Carlos1,Yang Chunsong2,Alanen Heli I.1,Eki Rebeka3,Abbas Tarek A.3,Maksimainen Mirko M.1,Glumoff Tuomo1,Duman Ramona4,Wagner Armin4,Paschal Bryce M.2,Lehtiö Lari1ORCID

Affiliation:

1. Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu University of Oulu Oulu Finland

2. Department of Biochemistry and Molecular Genetics University of Virginia Charlottesville Virginia USA

3. Department of Radiation Oncology University of Virginia Charlottesville Virginia USA

4. Diamond Light Source, Harwell Science and Innovation Campus Didcot UK

Abstract

AbstractDeltex 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 Å2 and a smaller one of 415 Å2. 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.

Funder

National Cancer Institute

Jane ja Aatos Erkon Säätiö

Biocenter, University of Oulu

Publisher

Wiley

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