Activation of PARP2/ARTD2 by DNA damage induces conformational changes relieving enzyme autoinhibition
| Autor: | Obaji, Ezeogo, Maksimainen, Mirko M., Galera-Prat, Albert, Lehtiö, Lari |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
DNA Repair
Protein Conformation Science DNA damage and repair Poly (ADP-Ribose) Polymerase-1 Nuclear Proteins DNA NAD Article Enzyme Activation Poly ADP Ribosylation Protein Domains Enzyme mechanisms Humans PolyADP-ribosylation DNA Breaks Double-Stranded Phosphorylation Poly(ADP-ribose) Polymerases Carrier Proteins X-ray crystallography DNA Damage Protein Binding Protein Unfolding |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-8 (2021) |
| Popis: | 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. Poly(ADP-ribose) polymerase 2 (PARP2) is activated by 5′-phosphorylated DNA breaks but the molecular mechanism is not fully understood. Here, the authors report a crystal structure of PARP2 bound to an activating DNA fragment, providing insights into the structural changes that lead to PARP2 activation. |
| Databáze: | OpenAIRE |
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