Structural basis for lack of ADP-ribosyltransferase activity in poly(ADP-ribose) polymerase-13/zinc finger antiviral protein.

The mammalian poly(ADP-ribose) polymerase family includes ADP-ribosyltransferases with diphtheria toxin homology (ARTD). Most members have mono-ADP-ribosyltransferase activity. also called zinc finger antiviral protein, has roles in viral immunity and microRNA-mediated stress responses. features a divergent homology domain missing a Pduanyu37 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 Pduanyu3713 and two of its functional partners in stress granules: and The crystal structure of the Pduanyu37 homology domain of Pduanyu3713 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 Pduanyu3713 did not result in 3-aminobenzamide binding, but in further closure of the site. Three-dimensional alignment of the Pduanyu37 homology domains of and illustrates placement of Pduanyu3713 residues that deviate from the Pduanyu37 family consensus. Introducing either one of two of these side chains into the corresponding positions in Pduanyu3715 abolished Pduanyu3715 ADP-ribosyltransferase activity. Taken together, our results show that Pduanyu3713 lacks the structural requirements for ADP-ribosyltransferase activity.

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