Obaji, E., Maksimainen, M.M., Galera-Prat, A. et al. Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition. Nat Commun 12, 3479 (2021). https://doi.org/10.1038/s41467-021-23800-x
Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition
|Author:||Obaji, Ezeogo1; Maksimainen, Mirko M.1; Galera-Prat, Albert1;|
1Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 3.2 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021090945662
|Publish Date:|| 2021-09-09
Human PARP2/ARTD2 is an ADP-ribosyltransferase which, when activated by 5′-phosphorylated DNA ends, catalyses poly-ADP-ribosylation of itself, other proteins and DNA. In this study, a crystal structure of PARP2 in complex with an activating 5′-phosphorylated DNA shows that the WGR domain bridges the dsDNA gap and joins the DNA ends. This DNA binding results in major conformational changes, including reorganization of helical fragments, in the PARP2 regulatory domain. A comparison of PARP1 and PARP2 crystal structures reveals how binding to a DNA damage site leads to formation of a catalytically competent conformation. In this conformation, PARP2 is capable of binding substrate NAD⁺ and histone PARylation factor 1 that changes PARP2 residue specificity from glutamate to serine when initiating DNA repair processes. The structure also reveals how the conformational changes in the autoinhibitory regulatory domain would promote the flexibility needed by the enzyme to reach the target macromolecule for ADP-ribosylation.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work was funded by the Jane and Aatos Erkko Foundation and the Academy of Finland (grant nos. 287063, 294085 and 319299 to L.L.). The use of the facilities of the Biocenter Oulu Structural Biology core facility, member of Biocenter Finland, Instruct-ERIC Centre Finland and FINStruct, as well as of Proteomics and Protein Analysis and Sequencing core facilities are gratefully acknowledged.
|Academy of Finland Grant Number:||
287063 (Academy of Finland Funding decision)
294085 (Academy of Finland Funding decision)
319299 (Academy of Finland Funding decision)
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