title: Conformational activation of poly(ADP-ribose) polymerase-1 upon DNA binding revealed by small-angle X-ray scattering.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear protein that plays key roles in several fundamental cellular processes. PARP-1 catalyzes the polymerization of nicotinamide adenine dinucleotide on itself and other acceptor proteins, forming long branched poly(ADP-ribose) polymers. The catalytic activity of PARP-1 is stimulated upon binding to damaged DNA, but how this signal is transmitted from the N-terminal DNA binding domain to the C-terminal catalytic domain in the context of the full-length enzyme is unknown. In this paper, small-angle X-ray scattering experiments and molecular dynamics simulations were used to gain insight into the conformational changes that occur during the catalytic activation of PARP-1 by an 8-mer DNA ligand. The data are consistent with a model in which binding of the DNA ligand establishes interdomain interactions between the DNA binding and catalytic domains, which induces an allosteric change in the active site that promotes catalysis. Moreover, the PARP-1-8-mer complex is seen to adopt a conformation that is poised to recruit DNA repair factors to the site of DNA damage. This study provides the first structural information about the DNA-induced conformational activation of full-length PARP-1.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, Department of Chemistry, and Institute of Cellular and Molecular Biology, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Steven O
authors.initials: SO
authors.lastname: Mansoorabadi
authors.forename: Meilan
authors.initials: M
authors.lastname: Wu
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Tao
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.forename: Sai Venkatesh
authors.initials: SV
authors.lastname: Pingali
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Hung-wen
authors.initials: HW
authors.lastname: Liu
mesh_terms: D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D053838:Scattering, Small Angle; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases