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Structural Basis for Lack of ADP-ribosyltransferase Activity in Poly(ADP-ribose) Polymerase-13/Zinc Finger Antiviral Protein
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 12, 7336-7344 p.Article in journal (Refereed) Published
Abstract [en]

Background: PARP13 contains a divergent PARP homology ADP-ribosyltransferase domain of unknown function. Results: The consensus NAD(+) pocket of PARP13 is occluded by interacting protein side chains. Conclusion: PARP13 lacks the structural requirements for NAD(+) binding. Significance: Evolutionary conservation of enzymatic inactivity suggests a need for a rigid domain structure.

The mammalian poly(ADP-ribose) polymerase (PARP) family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. PARP13/ARTD13, also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. PARP13 features a divergent PARP homology domain missing a PARP consensus sequence motif; the domain has enigmatic functions and apparently lacks catalytic activity. We used x-ray crystallography, molecular dynamics simulations, and biochemical analyses to investigate the structural requirements for ADP-ribosyltransferase activity in human PARP13 and two of its functional partners in stress granules: PARP12/ARTD12, and PARP15/BAL3/ARTD7. The crystal structure of the PARP homology domain of PARP13 shows obstruction of the canonical active site, precluding NAD(+) binding. Molecular dynamics simulations indicate that this closed cleft conformation is maintained in solution. Introducing consensus side chains in PARP13 did not result in 3-aminobenzamide binding, but in further closure of the site. Three-dimensional alignment of the PARP homology domains of PARP13, PARP12, and PARP15 illustrates placement of PARP13 residues that deviate from the PARP family consensus. Introducing either one of two of these side chains into the corresponding positions in PARP15 abolished PARP15 ADP-ribosyltransferase activity. Taken together, our results show that PARP13 lacks the structural requirements for ADP-ribosyltransferase activity.

Place, publisher, year, edition, pages
2015. Vol. 290, no 12, 7336-7344 p.
Keyword [en]
ADP-ribosylation, Molecular Dynamics, Post-translational Modification (PTM), Virus, X-ray ystallography
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:umu:diva-102361DOI: 10.1074/jbc.M114.630160ISI: 000351613600002PubMedID: 25635049OAI: diva2:815230
Available from: 2015-05-29 Created: 2015-04-23 Last updated: 2015-05-29Bibliographically approved

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Andersson, C. DavidLinusson, Anna
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