Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15

Nat Commun. 2025 Oct 29;16(1):9567. doi: 10.1038/s41467-025-65315-9.

Carmen Ebenwaldner ¹, Antonio Ginés García Saura ¹, Simon Ekström ², Katja Bernfur ¹, Martin Moche ³, Derek T Logan ¹, Michael S Cohen ⁴, Herwig Schüler ⁵

Affiliations

1 Division of Biochemistry and Structural Biology, Department of Chemistry, Lund University, Lund, Sweden.
2 SciLifeLab and BioMS, Integrated Structural Biology platform, Structural Proteomics Unit Sweden, Lund University, Lund, Sweden.
3 Protein Science Facility, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
4 Department of Chemical Physiology and Biochemistry, Oregon Health and Science University, Portland, OR, USA.
5 Division of Biochemistry and Structural Biology, Department of Chemistry, Lund University, Lund, Sweden. [email protected].

PMID: 41162413 DOI: 10.1038/s41467-025-65315-9

Abstract

PARP15 is a mono-ADP-ribosyltransferase that targets an unknown set of proteins as well as RNA. Its evolutionary relationship with PARP14 suggests roles in Antiviral defence; its localization to stress granules points to functions in the regulation of translation. Here we show that the transferase domain of PARP15 dimerizes in solution; the formation of dimers is a prerequisite for catalytic activity and monomeric mutant variants of the domain are inactive. In cells, dimer-disrupting mutations abrogate catalytic activity and alter the subcellular localization of the full-length protein. Using biophysical methods, including X-ray crystallography and HDX-MS, we provide evidence for a regulatory mechanism by which dimerization enables correct target engagement rather than NAD⁺ co-substrate binding, and by which the two protomers of the dimer operate independently of one another. Together, our results uncover a regulatory mechanism in a PARP family enzyme.

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