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

Ebenwaldner, Carmen LU orcid ; García Saura, Antonio Ginés LU ; Ekström, Simon LU ; Bernfur, Katja LU ; Moche, Martin ; Logan, Derek T. LU orcid ; Cohen, Michael S. and Schüler, Herwig LU orcid (2025) In Nature Communications 16.
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... (More)

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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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
16
article number
9567
pages
17 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105020278137
  • pmid:41162413
ISSN
2041-1723
DOI
10.1038/s41467-025-65315-9
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2025.
id
711bdf09-1e49-4fe6-92ec-8a965db4b69c
date added to LUP
2025-11-10 09:13:01
date last changed
2025-11-14 03:29:32
@article{711bdf09-1e49-4fe6-92ec-8a965db4b69c,
  abstract     = {{<p>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<sup>+</sup> 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.</p>}},
  author       = {{Ebenwaldner, Carmen and García Saura, Antonio Ginés and Ekström, Simon and Bernfur, Katja and Moche, Martin and Logan, Derek T. and Cohen, Michael S. and Schüler, Herwig}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Regulation of ADP-ribosyltransferase activity by ART domain dimerization in PARP15}},
  url          = {{http://dx.doi.org/10.1038/s41467-025-65315-9}},
  doi          = {{10.1038/s41467-025-65315-9}},
  volume       = {{16}},
  year         = {{2025}},
}