Binding of Sulphonated Indigo Derivatives to RepA-WH1 Inhibits DNA-induced Protein Amyloidogenesis

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2008 Feb 21

PMID 18285361

Citations 12

Authors

Fatima Gasset-Rosa

Maria Jesus Mate

Cristina Davila-Fajardo

Jeronimo Bravo

Rafael Giraldo

Affiliations

Soon will be listed here.

Abstract

The quest for inducers and inhibitors of protein amyloidogenesis is of utmost interest, since they are key tools to understand the molecular bases of proteinopathies such as Alzheimer, Parkinson, Huntington and Creutzfeldt-Jakob diseases. It is also expected that such molecules could lead to valid therapeutic agents. In common with the mammalian prion protein (PrP), the N-terminal Winged-Helix (WH1) domain of the pPS10 plasmid replication protein (RepA) assembles in vitro into a variety of amyloid nanostructures upon binding to different specific dsDNA sequences. Here we show that di- (S2) and tetra-sulphonated (S4) derivatives of indigo stain dock at the DNA recognition interface in the RepA-WH1 dimer. They compete binding of RepA to its natural target dsDNA repeats, found at the repA operator and at the origin of replication of the plasmid. Calorimetry points to the existence of a major site, with micromolar affinity, for S4-indigo in RepA-WH1 dimers. As revealed by electron microscopy, in the presence of inducer dsDNA, both S2/S4 stains inhibit the assembly of RepA-WH1 into fibres. These results validate the concept that DNA can promote protein assembly into amyloids and reveal that the binding sites of effector molecules can be targeted to inhibit amyloidogenesis.

Citing Articles

Mechanisms of Theta Plasmid Replication in Enterobacteria and Implications for Adaptation to Its Host.

Kim J, Bugata V, Cortes-Cortes G, Quevedo-Martinez G, Camps M EcoSal Plus. 2020; 9(1).

PMID: 33210586 PMC: 7724965. DOI: 10.1128/ecosalplus.ESP-0026-2019.

SynBio and the Boundaries between Functional and Pathogenic RepA-WH1 Bacterial Amyloids.

Giraldo R mSystems. 2020; 5(3).

PMID: 32606029 PMC: 7329326. DOI: 10.1128/mSystems.00553-20.

Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells.

Revilla-Garcia A, Fernandez C, Moreno-Del Alamo M, de Los Rios V, Vorberg I, Giraldo R mBio. 2020; 11(2).

PMID: 32291306 PMC: 7157824. DOI: 10.1128/mBio.02937-19.

Outlining Core Pathways of Amyloid Toxicity in Bacteria with the RepA-WH1 Prionoid.

Molina-Garcia L, Moreno-Del Alamo M, Botias P, Martin-Moldes Z, Fernandez M, Sanchez-Gorostiaga A Front Microbiol. 2017; 8:539.

PMID: 28421043 PMC: 5378768. DOI: 10.3389/fmicb.2017.00539.

Functional amyloids as inhibitors of plasmid DNA replication.

Molina-Garcia L, Gasset-Rosa F, Moreno-Del Alamo M, Fernandez-Tresguerres M, de la Espina S, Lurz R Sci Rep. 2016; 6:25425.

PMID: 27147472 PMC: 4857107. DOI: 10.1038/srep25425.

References

Wiseman T, Williston S, Brandts J, Lin L . Rapid measurement of binding constants and heats of binding using a new titration calorimeter. Anal Biochem. 1989; 179(1):131-7. DOI: 10.1016/0003-2697(89)90213-3. View

Giraldo R, Fernandez-Tornero C, Evans P, Diaz-Orejas R, Romero A . A conformational switch between transcriptional repression and replication initiation in the RepA dimerization domain. Nat Struct Biol. 2003; 10(7):565-71. DOI: 10.1038/nsb937. View

Lima L, Cordeiro Y, Tinoco L, Marques A, Oliveira C, Sampath S . Structural insights into the interaction between prion protein and nucleic acid. Biochemistry. 2006; 45(30):9180-7. DOI: 10.1021/bi060532d. View

Nandi P, Leclerc E, Nicole J, Takahashi M . DNA-induced partial unfolding of prion protein leads to its polymerisation to amyloid. J Mol Biol. 2002; 322(1):153-61. DOI: 10.1016/s0022-2836(02)00750-7. View

King D, Safar J, Legname G, Prusiner S . Thioaptamer interactions with prion proteins: sequence-specific and non-specific binding sites. J Mol Biol. 2007; 369(4):1001-14. DOI: 10.1016/j.jmb.2007.02.004. View

Prusiner S . Prions. Proc Natl Acad Sci U S A. 1998; 95(23):13363-83. PMC: 33918. DOI: 10.1073/pnas.95.23.13363. View

Cordeiro Y, Machado F, Juliano L, Juliano M, Brentani R, Foguel D . DNA converts cellular prion protein into the beta-sheet conformation and inhibits prion peptide aggregation. J Biol Chem. 2001; 276(52):49400-9. DOI: 10.1074/jbc.M106707200. View

Geoghegan J, Valdes P, Orem N, Deleault N, Williamson R, Harris B . Selective incorporation of polyanionic molecules into hamster prions. J Biol Chem. 2007; 282(50):36341-53. PMC: 3091164. DOI: 10.1074/jbc.M704447200. View

Nieto C, Giraldo R, Diaz R . Genetic and functional analysis of the basic replicon of pPS10, a plasmid specific for Pseudomonas isolated from Pseudomonas syringae patovar savastanoi. J Mol Biol. 1992; 223(2):415-26. DOI: 10.1016/0022-2836(92)90661-3. View

10.

Giraldo R, Fernandez-Tresguerres M . Twenty years of the pPS10 replicon: insights on the molecular mechanism for the activation of DNA replication in iteron-containing bacterial plasmids. Plasmid. 2004; 52(2):69-83. DOI: 10.1016/j.plasmid.2004.06.002. View

11.

McGovern S, Caselli E, Grigorieff N, Shoichet B . A common mechanism underlying promiscuous inhibitors from virtual and high-throughput screening. J Med Chem. 2002; 45(8):1712-22. DOI: 10.1021/jm010533y. View

12.

Jelesarov I, Bosshard H . Isothermal titration calorimetry and differential scanning calorimetry as complementary tools to investigate the energetics of biomolecular recognition. J Mol Recognit. 1999; 12(1):3-18. DOI: 10.1002/(SICI)1099-1352(199901/02)12:1<3::AID-JMR441>3.0.CO;2-6. View

13.

Nandi P, Nicole J . Nucleic acid and prion protein interaction produces spherical amyloids which can function in vivo as coats of spongiform encephalopathy agent. J Mol Biol. 2004; 344(3):827-37. DOI: 10.1016/j.jmb.2004.09.080. View

14.

Necula M, Kayed R, Milton S, Glabe C . Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem. 2007; 282(14):10311-24. DOI: 10.1074/jbc.M608207200. View

15.

Diaz-Lopez T, Lages-Gonzalo M, Serrano-Lopez A, Alfonso C, Rivas G, Diaz-Orejas R . Structural changes in RepA, a plasmid replication initiator, upon binding to origin DNA. J Biol Chem. 2003; 278(20):18606-16. DOI: 10.1074/jbc.M212024200. View

16.

Deleault N, Geoghegan J, Nishina K, Kascsak R, Williamson R, Supattapone S . Protease-resistant prion protein amplification reconstituted with partially purified substrates and synthetic polyanions. J Biol Chem. 2005; 280(29):26873-9. DOI: 10.1074/jbc.M503973200. View

17.

Nakamura A, Wada C, Miki K . Structural basis for regulation of bifunctional roles in replication initiator protein. Proc Natl Acad Sci U S A. 2007; 104(47):18484-9. PMC: 2141803. DOI: 10.1073/pnas.0705623104. View

18.

Chiti F, Dobson C . Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006; 75:333-66. DOI: 10.1146/annurev.biochem.75.101304.123901. View

19.

Garcia de Viedma D, Giraldo R, Lurz R, Diaz-Orejas R . Transcription of repA, the gene of the initiation protein of the Pseudomonas plasmid pPS10, is autoregulated by interactions of the RepA protein at a symmetrical operator. J Mol Biol. 1995; 247(2):211-23. DOI: 10.1006/jmbi.1994.0134. View

20.

Cohen T, Frydman-Marom A, Rechter M, Gazit E . Inhibition of amyloid fibril formation and cytotoxicity by hydroxyindole derivatives. Biochemistry. 2006; 45(15):4727-35. DOI: 10.1021/bi051525c. View