Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS

Colanzi, Antonino; Grimaldi, Giovanna; Catara, Giuliana; Valente, Carmen; Cericola, Claudia; Liberali, Prisca; Ronci, Maurizio; Lalioti, Vassiliki; Bruno, Agostino; Beccari, Andrea R.; Urbani, Andrea; Flora, Antonio De; Nardini, M.; Bolognesi, Martino; Luini, Alberto; Corda, Daniela

doi:10.1073/pnas.1222413110

Cited by 39 publications

(47 citation statements)

References 42 publications

(57 reference statements)

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“…2). This Trp has recently been implicated both as a dimerization switch in CtBP1[38] and in models of the binding of the brefeldin A (BFA) moiety in the BFA-ADP ribosyl conjugate of rat CtBP1/BARS[39]. Interestingly, the MTOB S8 atom centers over the CtBP Trp318/324 indole, rather than orienting its lone pair of electrons towards the positively charged CtBP Arg97/103, suggesting a sulfur-π interaction [40,41].…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

et al. 2014

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The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory D-isomer specific 2-hydroxyacid dehydrogenase (D2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD+ revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD+ phosphate. Neither feature is present in other D2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors.

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Section: Resultsmentioning

confidence: 99%

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

et al. 2014

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“…BARS are localized in the cytosol and have a role in membrane trafficking and Golgi fission (Spano et al, 1999; Colanzi et al, 2013). CtBP was first described as a human protein that interacts with C-terminal sequences Pro-X-Asp-Leu-Ser (PXDLS) of adenovirus E1A protein (Schaeper et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

ANGUSTIFOLIA, a Plant Homolog of CtBP/BARS Localizes to Stress Granules and Regulates Their Formation

Bhasin

Hülskamp

2017

Front. Plant Sci.

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The ANGUSTIFOLIA (AN) gene in Arabidopsis is important for a plethora of morphological phenotypes. Recently, AN was also reported to be involved in responses to biotic and abiotic stresses. It encodes a homolog of the animal C-terminal binding proteins (CtBPs). In contrast to animal CtBPs, AN does not appear to function as a transcriptional co-repressor and instead functions outside nucleus where it might be involved in Golgi-associated membrane trafficking. In this study, we report a novel and unexplored role of AN as a component of stress granules (SGs). Interaction studies identified several RNA binding proteins that are associated with AN. AN co-localizes with several messenger ribonucleoprotein granule markers to SGs in a stress dependent manner. an mutants exhibit an altered SG formation. We provide evidence that the NAD(H) binding domain of AN is relevant in this context as proteins carrying mutations in this domain localize to a much higher degree to SGs and strongly reduce AN dimerization and its interaction with one interactor but not the others. Finally, we show that AN is a negative regulator of salt and osmotic stress responses in Arabidopsis suggesting a functional relevance in SGs.

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“…In the nucleus, members of the CtBP protein family act as transcription co-repressors, and thus regulate numerous cellular functions, including epithelial differentiation, tumourigenesis and apoptosis [279]. The BFA-dependent ADPr of CtBP1-S/BARS is a non-classical two-step reaction [280]. The first step is a novel form of ADPr of a small molecule resulting from the covalent binding of ADP-ribose derived from NAD + or cyclic ADPribose to BFA.…”

Section: The Bfa-mediated Adp-ribosylation-like Reactionmentioning

confidence: 99%

Targeting ADP-ribosylation as an antimicrobial strategy

Catara

Corteggio

Valente

et al. 2019

Biochemical Pharmacology

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A B S T R A C T ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules controlling major biological processes as diverse as DNA damage repair, transcriptional regulation, intracellular transport, immune and stress responses, cell survival and proliferation. Furthermore, enzymatic reactions of ADPr are central in the pathogenesis of many human diseases, including infectious conditions. By providing a review of ADPr signalling in bacterial systems, we highlight the relevance of this chemical modification in the pathogenesis of human diseases depending on host-pathogen interactions. The post-antibiotic era has raised the need to find alternative approaches to antibiotic administration, as major pathogens becoming resistant to antibiotics. An in-depth understanding of ADPr reactions provides the rationale for designing novel antimicrobial strategies for treatment of infectious diseases. In addition, the understanding of mechanisms of ADPr by bacterial virulence factors offers important hints to improve our knowledge on cellular processes regulated by eukaryotic homologous enzymes, which are often involved in the pathogenesis of human diseases.T large number of worldwide spread diseases, affecting humans, insects and plants [31,[56][57][58], with a great impact on human health. In addition, infectious diseases strongly affect the world economy in terms of costs for the human health as well as food and agricultural economic losses [59]. The use of antibiotics to counteract the pathogen infections has represented the therapeutic strategy of choice in the last century, however the emergence of antibiotic resistance strains represents the major challenge of the 21st century [60][61][62]. Targeting bacterial pathogenic mechanisms by disarming pathogens of virulence factors, for instance by inhibiting the enzymatic activity of bART, represents a valid alternative intervention strategy to overcome antibiotic resistance [63][64][65][66]. In addition, because of the conservation of ADPr systems throughout the evolution, the understanding of bacterial pathogenic mechanisms may contribute to unveil novel and conserved cellular processes regulated by ADPr in high organisms [34,45,67,68]. The dysregulation of such processes can be either cause of human diseases or be target of therapeutic intervention [39,[69][70][71].Herein, we will provide a summary of bacterial ADPr systems describing their pathogenic mechanisms and highlighting the similarities with ADPr systems in mammals as well. Further, we discuss the potential of targeting ADPr for therapeutic strategies of infection diseases. ADP-ribosylation in pathophysiologyADPr was originally described in the 60s; two independent studies reported the identification of a new polymer, poly(ADP-ribose) (PAR) synthesised from NAD + in vertebrate cells [72] and, simultaneously, the finding that bacterial DTX activity from C. diphteriae is dependent on NAD + content [73]. In the following decades, research in the field has expanded the involvement of ADPr ...

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Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS

Cited by 39 publications

References 42 publications

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design

ANGUSTIFOLIA, a Plant Homolog of CtBP/BARS Localizes to Stress Granules and Regulates Their Formation

Targeting ADP-ribosylation as an antimicrobial strategy

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