Structure of the Ecto-ADP-ribosyl Transferase ART2.2 from Rat

Mueller-Dieckmann, Christoph; Ritter, H.; Haag, Friedrich; Koch-Nolte, Friedrich; Schulz, Georg E.

doi:10.1016/s0022-2836(02)00818-5

Cited by 55 publications

(77 citation statements)

References 35 publications

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“…This accounts for the ADP-ribosylation reaction in other type IV ADPRTs. Given the large extent of structural similarity, the structure of our complex also is likely to provide an insight into the reaction mechanisms of type III ADPRTs (28,29) and mammalian ecto-ADP-ribosyltransferase (30). Furthermore, NAD structures also are similar in all ADPRTs, sharing a compact and energetically unfavorable conformation (31).…”

Section: Common Reaction Mechanisms Based On Structural Relations Withmentioning

confidence: 88%

Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin

Tsuge

Nagahama

Oda

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

109

144

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The ADP-ribosylating toxins (ADPRTs) produced by pathogenic bacteria modify intracellular protein and affect eukaryotic cell function. Actin-specific ADPRTs (including Clostridium perfringens -toxin and Clostridium botulinum C2 toxin) ADP-ribosylate G-actin at Arg-177, leading to disorganization of the cytoskeleton and cell death. Although the structures of many actin-specific ADPRTs are available, the mechanisms underlying actin recognition and selective ADP-ribosylation of Arg-177 remain unknown. Here we report the crystal structure of actin-Ia in complex with the nonhydrolyzable NAD analog ␤TAD at 2.8 Å resolution. The structure indicates that Ia recognizes actin via five loops around NAD: loop I (Tyr-60 -Tyr-62 in the N domain), loop II (active-site loop), loop III, loop IV (PN loop), and loop V (ADP-ribosylating turn-turn loop). We used site-directed mutagenesis to confirm that loop I on the N domain and loop II are essential for the ADP-ribosyltransferase activity. Furthermore, we revealed that Glu-378 on the EXE loop is in close proximity to Arg-177 in actin, and we proposed that the ADPribosylation of Arg-177 proceeds by an SN1 reaction via first an oxocarbenium ion intermediate and second a cationic intermediate by alleviating the strained conformation of the first oxocarbenium ion. Our results suggest a common reaction mechanism for ADPRTs. Moreover, the structure might be of use in rational drug design to block toxin-substrate recognition.complex ͉ crystal structure ͉ protein recognition

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Section: Common Reaction Mechanisms Based On Structural Relations Withmentioning

confidence: 88%

Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin

Tsuge

Nagahama

Oda

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

109

144

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“…PARP-2, and rat ART2.2) have provided fascinating insights into the structure and function of ADP-ribosylating enzymes (22)(23)(24)(25)(26)(27). In contrast, very little is known about the structure and function of the enzymes catalyzing protein de-ADP-ribosylation (18,21,28).…”

Section: Figmentioning

confidence: 99%

The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation

Mueller-Dieckmann

Kernstock²,

Lisurek

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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136

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Posttranslational modifications are used by cells from all kingdoms of life to control enzymatic activity and to regulate protein function. For many cellular processes, including DNA repair, spindle function, and apoptosis, reversible mono-and polyADP-ribosylation constitutes a very important regulatory mechanism. Moreover, many pathogenic bacteria secrete toxins which ADP-ribosylate human proteins, causing diseases such as whooping cough, cholera, and diphtheria. Whereas the 3D structures of numerous ADP-ribosylating toxins and related mammalian enzymes have been elucidated, virtually nothing is known about the structure of protein de-ADP-ribosylating enzymes. Here, we report the 3D structure of human ADP-ribosylhydrolase 3 (hARH3). The molecular architecture of hARH3 constitutes the archetype of an all-␣-helical protein fold and provides insights into the reversibility of protein ADP-ribosylation. Two magnesium ions flanked by highly conserved amino acids pinpoint the active-site crevice. Recombinant hARH3 binds free ADP-ribose with micromolar affinity and efficiently de-ADP-ribosylates poly-but not monoADP-ribosylated proteins. Docking experiments indicate a possible binding mode for ADP-ribose polymers and suggest a reaction mechanism. Our results underscore the importance of endogenous ADP-ribosylation cycles and provide a basis for structure-based design of ADP-ribosylhydrolase inhibitors.protein structure ͉ posttranslational modification ͉ glycohydrolase ͉ docking P osttranslational modifications (PTMs) are covalent modifications of amino acid side chains in proteins that come in many different sizes and shapes, ranging from the simple addition of a phosphate group to complex multistep glycosylations. Enzyme-catalyzed PTMs allow rapid responses to environmental stimuli and play crucial roles in signal transduction. NAD-dependent ADP-ribosylation is a reversible PTM in which mono-and polyADP-ribosyltransferases (ARTs and PARPs) and ADP-ribosylhydrolases (ARHs) and poly(ADP-ribose) glycohydrolases (PARGs) catalyze amino acid-specific ADPribosylation and de-ADP-ribosylation, respectively ( Fig. 1) (1-10). ADP-ribosylation has attracted attention because bacterial virulence factors, including diphtheria, cholera, and pertussis toxin, use it as part of their pathogenic mechanism (2, 11). Mono-and polyADP-ribosylation have been recognized also as regulatory mechanisms in many cellular processes, including DNA-repair, chromatin decondensation, transcription, telomere function, mitotic spindle formation, and apoptosis (5-10, 12).Several enzymes have been cloned that catalyze de-ADPribosylation of mono-or polyADP-ribosylated proteins (13-15). Dinitrogenase-activating glycohydrolase (DRAG), an Arg-specific ARH from the phototrophic bacterium Rhodospirillum rubrum, regulates a key enzyme of nitrogen fixation (16-18). The human genome encodes three DRAG-related proteins designated ARH1, ARH2, and ARH3 (19), which are 357, 354, and 363 residues long, respectively. ARH1, like DRAG, specifically de-ADP-ribosylates prote...

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“…HopU1 shares sequence similarity to mADP-RTs in animal pathogens and eukaryotes belonging to the CT group. Several structures of this large family of proteins have been determined (27)(28)(29).…”

mentioning

confidence: 99%

Structure Function Analysis of an ADP-ribosyltransferase Type III Effector and Its RNA-binding Target in Plant Immunity

Jeong

Lin

Joe

et al. 2011

Journal of Biological Chemistry

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Background: HopU1 ADP-ribosylates GRP7, suppressing plant immunity. Results: The HopU1 structure has two novel loops required for GRP7 recognition, and HopU1 ribosylates GRP7 at an arginine in position 49 disrupting its function. Conclusion: HopU1 targets a conserved arginine in GRP7, disabling its ability to bind immunity-related RNA. Significance: The mechanistic details of how HopU1 recognizes its substrate reveal how HopU1 contributes to pathogenesis.

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Structure of the Ecto-ADP-ribosyl Transferase ART2.2 from Rat

Cited by 55 publications

References 35 publications

Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin

Structural basis of actin recognition and arginine ADP-ribosylation by Clostridium perfringens ι-toxin

The structure of human ADP-ribosylhydrolase 3 (ARH3) provides insights into the reversibility of protein ADP-ribosylation

Structure Function Analysis of an ADP-ribosyltransferase Type III Effector and Its RNA-binding Target in Plant Immunity

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