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Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS
- Source :
- Proceedings of the National Academy of Sciences of the United States of America 110 (2013): 9794–9799. doi:10.1073/pnas.1222413110., info:cnr-pdr/source/autori:Colanzi A, Grimaldi G, Catara G, Valente C, Cericola C, Liberali P, Ronci M, Lalioti VS, Bruno A, Beccari AR, Urbani A, De Flora A, Nardini M, Bolognesi M, Luini A, Corda D./titolo:Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1%2FBARS./doi:10.1073%2Fpnas.1222413110./rivista:Proceedings of the National Academy of Sciences of the United States of America/anno:2013/pagina_da:9794/pagina_a:9799/intervallo_pagine:9794–9799/volume:110, Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2013
- Publisher :
- National Academy of Sciences (U.S.), 2013.
-
Abstract
- ADP-ribosylation is a posttranslational modification that modulates the functions of many target proteins. We previously showed that the fungal toxin brefeldin A (BFA) induces the ADP-ribosylation of C-terminal-binding protein-1 short-form/BFA-ADP-ribosylation substrate (CtBP1-S/BARS), a bifunctional protein with roles in the nucleus as a transcription factor and in the cytosol as a regulator of membrane fission during intracellular trafficking and mitotic partitioning of the Golgi complex. Here, we report that ADP-ribosylation of CtBP1-S/BARS by BFA occurs via a nonconventional mechanism that comprises two steps: (i) synthesis of a BFA-ADP-ribose conjugate by the ADP-ribosyl cyclase CD38 and (ii) covalent binding of the BFA-ADP-ribose conjugate into the CtBP1-S/BARS NAD+-binding pocket. This results in the locking of CtBP1-S/BARS in a dimeric conformation, which prevents its binding to interactors known to be involved in membrane fission and, hence, in the inhibition of the fission machinery involved in mitotic Golgi partitioning. As this inhibition may lead to arrest of the cell cycle in G2, these findings provide a strategy for the design of pharmacological blockers of cell cycle in tumor cells that express high levels of CD38.<br />We thank all colleagues who kindly provided antibodies and reagents; Dr. J. Donaldson (National Institutes of Health) for BFA analogs; Dr. C. P. Berrie for editorial assistance; and Drs. C. Limina, A. Tamburro, M. G. Silletta, R. Weigert, and S. Spanò (Negri Sud Institute) for performing initial experiments. We also acknowledge financial support from Italian Association for Cancer Research (AIRC) through the Grants IG4664 and IG10341 (to D.C.), IG4700 (to A.L.), and IG6074 (to A.C.); and from the Liguria Region and the Ministry of Education, University, and Research (Fund for Investments in Basic Research Project; A.D.F.). G.G. and C.V. received fellowships from AIRC (Italian Foundation for Cancer Research). Financial support from Technological Innovation Fund DM 24/09/2009, Legge 46/82-MEF, and Project FaReBio di Qualità also is acknowledged
- Subjects :
- Models, Molecular
anticancer molecules
chemistry.chemical_compound
Cytosol
Membrane fission
Competitive
Models
Multidisciplinary
Membrane Glycoproteins
Blotting
Settore BIO/12
Cell cycle
Brefeldin A
Biological Sciences
Cell biology
DNA-Binding Proteins
ADP-ribosylation
symbols
mitosis
Animals
HeLa Cells
Humans
Protein Processing, Post-Translational
Alcohol Oxidoreductases
Antigens, CD38
Protein Binding
Binding Sites
Rats
ADP-ribosyl Cyclase
Blotting, Western
NAD
cell signaling
Golgi fragmentation
Binding, Competitive
Protein Structure, Tertiary
Adenosine Diphosphate Ribose
Western
Intracellular
Protein Structure
Biology
symbols.namesake
Antigens
Mitosis
Protein Processing
Post-Translational
Molecular
Golgi apparatus
Binding
ADP-ribosyl Cyclase 1
chemistry
CD38
Tertiary
Subjects
Details
- ISSN :
- 00278424
- Database :
- OpenAIRE
- Journal :
- PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110: 9794-9799 (2013)
- Accession number :
- edsair.doi.dedup.....a75629932b21a36f4246d3c24e8633f0