1. Structures and Mechanisms of Enzymes Employed in the Synthesis and Degradation of PARP-Dependent Protein ADP-Ribosylation 
Eva Barkauskaite, Gytis Jankevicius, Ivan Ahel 
Molecular Cell 
Volume 58, Issue 6, Pages (June 2015)
DOI: /j.molcel
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2. Figure 1 PARP-Dependent ADP-Ribosylation Cycle
Proteins are ADP-ribosylated by PARPs using NAD+ as a co-factor, releasing nicotinamide (NA). Specific PARPs can ADP-ribosylate previous ADP-ribose (ADPr) units, which results in poly(ADP-ribose) formation with occasional branching. Different domains recognize mono-ADP-ribose or poly(ADP-ribose). Macrodomain recognition parts of mono-ADP-ribose and poly(ADP-ribose) are indicated in orange. PAR recognition parts of WWE domain are highlighted in violet and those of PBZs in green. Poly(ADP-ribosyl)ated proteins can be substrates of TARG1, which can remove whole PAR chain from the targets, or of PARG, which degrades PAR, leaving mono-ADP-ribosylated protein. Mono-ADP-ribose can be removed by the action of MacroD1, MacroD2, or TARG1, which complete the ADP-ribosylation cycle.
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3. Figure 2 Domain Architecture of Human PARPs
PARP1–16 with alternative names listed on the side domain structures. ARTD, ADP-ribosyl transferase diphtheria type; vPARP, vault PARP; TNKS, Tankyrase; TIPARP, TCDD inducible PARP; BAL, B cell aggressive lymphoma; ZC3HDC1, zinc finger CCCH-type domain containing 1; ZC3HAV1, zinc finger CCCH-type antiviral 1; ZAP, zinc finger antiviral protein. Structural information availability of specific domains is indicated by PDB code under the specific domains. The number of amino acids composing the protein is indicated on the right. The following domain names were used: ZnF, zinc finger; BRCT, BRCA1 C-terminal; WGR, conserved Trp-Gly-Arg motif domain; HD, helical domain; ART, ADP-ribosyl transferase; VIT, vault protein inter-alpha-trypsin; vWFA, von Willebrand type A; ANK, ankyrin; SAM, sterile alpha motif; CCCH ZnF, CCCH type zinc finger; WWE, three conserved residues W-W-E motif domain; Macro, macrodomain; RRM, RNA recognition motif; UIM, ubiquitin interaction motif; TM, transmembrane motif.
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4. Figure 3 Representation of the PARP1 Active Site
The crystal structure of the essential PARP1 domains bound to the DNA double-strand break (PDB: 4DQY) is shown. Three PARP1 active site residues, His(H)-862, Tyr(Y)-896, and Glu(E)-988, are illustrated as atom colored sticks (carbon backbone shown in gray). The donor (D) loop is shown in magenta, and the acceptor loop is depicted in orange. The NAD+ (modeled based on the superposition of the human PARP-1 [PDB: 4DQY] structure with the diphtheria bacterial toxin [PDB: 1TOX] structure) is colored as green atom colored sticks and shows the binding of NAD+ to the donor site, while the ADP group, which is part of carba-NAD (modeled based on the superposition of the human PARP1 [PDB: 4DQY] structure with chicken PARP1 [PDB: 1A26] structures), is colored as blue atom colored sticks and shows the binding of ADP-ribose in the acceptor site.
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5. Figure 4
Domain Architecture of Human ADP-Ribosylation Removing Enzymes
Architectures of five main human enzymes involved in PARP-mediated ADP-ribosylation removal are depicted. Alternative protein names are listed on the right. ARH3, ADP-ribosyl hydrolase 3; PARG, poly(ADP-ribose) glycohydrolase; TARG1, terminal ADP-ribose glycohydrolase 1; OARD1, O-acetyl-ADP-ribose deacetylase 1; LRP16, leukemia related protein 16. ARH3 contains a catalytic domain of dinitrogenase reductase-activating glycohydrolase (DraG) family. PARG contains a regulatory region in addition to its catalytic (CAT) region. The latter comprises accessory domain (AD) and a macrodomain (Macro) fold domain.
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6. Figure 5 ADP-Ribose Processing Enzymes
(A–C) The three ADP-ribose processing macrodomains, (A) the catalytic region of PARG (macrodomain cyan Cα backbone; accessory domain, dark blue Cα backbone; PDB: 4B1H), (B) TARG1 (green Cα backbone; PDB: 4J5S), and (C) MacroD2 (magenta Cα backbone; PDB: 4IQY) are shown. The catalytic residues and the macrodomain loop, which ensures a strained substrate conformation, are colored in yellow and labeled accordingly. The PARG catalytic loop is colored in magenta with the key catalytic residue indicated. The N-ribose′ (adenine) and N-ribose″ (nicotinamide) are colored in yellow and green atom colored sticks, respectively. Please note that in TARG1 the aromatic residue found in MacroD1/D2 and PARG is replaced by an aspartate residue, which resolves the covalent TARG1 lysyl intermediate also shown in the image. The N-ribose 2′-OH position used to attach subsequent (N+1) and the 1″-OH position needed for adding of preceding (N-1) ADP-ribose groups in PARG are illustrated by blue and green circles, respectively. The 1″-OH position of TARG1 and MacroD2 where the acidic residue of acceptor protein would continue is indicated by arrows.
Molecular Cell  , DOI: ( /j.molcel )
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