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<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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Carmen Ebenwaldner,
  • Antonio Ginés García Saura,
  • Simon Ekström,
  • Katja Bernfur,
  • Martin Moche,
  • Derek T. Logan,
  • Michael S. Cohen,
  • Herwig Schüler

摘要

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.