In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs)

Otto, Helge; Reche, Pedro A.; Bazán, Fernando; Dittmar, Katharina; Haag, Friedrich; Koch-Nolte, Friedrich

doi:10.1186/1471-2164-6-139

Cited by 232 publications

(198 citation statements)

References 59 publications

(53 reference statements)

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“…There is a striking imbalance between the number of ADPribosylating and the number of de-ADP-ribosylating enzymes identified in mammals to date: Mammalian genomes typically encode 16-17 PARP-related and 4-6 ART2-related ADP-ribosyltransferases, but only three ARH-related and a single PARG-related ADP-ribosylhydrolases (19,37). The best characterized polyADPribosylpolymerases have been localized to the cell nucleus (PARP1 and PARP2, the tankyrases) and͞or cytosol (vault PARP and PARP-10); whereas the best characterized mono-ADP-ribosyltransferases are GPI-anchored (ART1 and ART2) or secreted ectoenzymes (ART5) (6,38).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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.

Self Cite

136

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“…We have previously excluded any role of the extracellular, membrane-associated ART enzymes (20) in endogenous G␤ subunit mono-ADP-ribosylation (4). The mammalian intracellular ART enzymes are only now beginning to be identified, and they include two sirtuins and novel members of the poly(ADP-ribose) polymerase (PARP) family (3,(21)(22)(23). Some of these PARP enzymes have been proposed to act as cellular mono-ADP-ribosyltransferases, and indeed, this has been demonstrated for PARP10 (24).…”

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confidence: 99%

Mono-ADP-ribosylation of the G Protein βγ Dimer Is Modulated by Hormones and Inhibited by Arf6

Dani

Mayo

Stilla

et al. 2011

Journal of Biological Chemistry

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Mono-ADP-ribosylation is a reversible post-translational modification that can modulate the functions of target proteins. We have previously demonstrated that the ␤ subunit of heterotrimeric G proteins is endogenously mono-ADP-ribosylated, and once modified, the ␤␥ dimer is inactive toward its effector enzymes. To better understand the physiological relevance of this post-translational modification, we have studied its hormonal regulation. Here, we report that G␤ subunit mono-ADP-ribosylation is differentially modulated by G protein-coupled receptors. In intact cells, hormone stimulation of the thrombin receptor induces G␤ subunit mono-ADP-ribosylation, which can affect G protein signaling. Conversely, hormone stimulation of the gonadotropin-releasing hormone receptor (GnRHR) inhibits G␤ subunit mono-ADP-ribosylation. We also provide the first demonstration that activation of the GnRHR can activate the ADP-ribosylation factor Arf6, which in turn inhibits G␤ subunit mono-ADP-ribosylation. Indeed, removal of Arf6 from purified plasma membranes results in loss of GnRHR-mediated inhibition of G␤ subunit mono-ADP-ribosylation, which is fully restored by re-addition of purified, myristoylated Arf6. We show that Arf6 acts as a competitive inhibitor of the endogenous ADP-ribosyltransferase and is itself modified by this enzyme. These data provide further understanding of the mechanisms that regulate endogenous ADP-ribosylation of the G␤ subunit, and they demonstrate a novel role for Arf6 in hormone regulation of G␤ subunit mono-ADP-ribosylation.Mono-ADP-ribosylation is a post-translational modification that is catalyzed by bacterial toxins and eukaryotic enzymes and consists of the transfer of the ADP-ribose moiety from ␤-NAD ϩ to a specific amino acid of various cellular proteins (1-3). We have previously demonstrated the occurrence of functional mono-ADP-ribosylation of the heterotrimeric G protein ␤ subunit (4, 5).The heterotrimeric G proteins are the most common transducers for G protein-coupled receptors (GPCRs), 4 the largest family of cell-surface receptors. They transduce biological signals from the cell surface to the intracellular compartment (6, 7). In the classical model of G protein signaling, when GPCRs are activated by ligand binding they catalyze the exchange of the tightly bound GDP for GTP on the ␣ subunit of the heterotrimeric G protein; the binding of GTP activates the G protein and the G␣ subunit dissociates from the G␤␥ dimer. Both the G␣ subunit and the G␤␥ dimer regulate effector proteins, including adenylyl cyclases, phospholipases, MAPK, and ion channels (see Refs. 8, 9 and references therein). Thus, although the G␤␥ dimers were once thought to only be negative regulators of G␣-dependent signaling, they are now well recognized as mediators of receptor signaling in their own right (8,9).We have previously demonstrated that a membrane-associated, arginine-specific mono-ADP-ribosyltransferase modifies residue 129 of the G␤ subunit when it is in its active heterodimeric conformation (4,5,10). This ...

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“…The polymerase catalyzes the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes, which affects cellular processes as diverse as replication, transcription, differentiation, gene regulation, protein degradation, and spindle maintenance. The first PARP enzyme was described over 40 years ago (1), and is the prototype for a superfamily of 17 members (2). PARP-1 is a nuclear protein whose zinc-finger DNA binding domain localizes PARP-1 to the site of DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology

Ratnam¹,

Low

2007

Clinical Cancer Research

270

214

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Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents.

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In silico characterization of the family of PARP-like poly(ADP-ribosyl)transferases (pARTs)

Cited by 232 publications

References 59 publications

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

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

Mono-ADP-ribosylation of the G Protein βγ Dimer Is Modulated by Hormones and Inhibited by Arf6

Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology

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