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Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides

Abstract

The lasso peptide microcin J25 is known to hijack the siderophore receptor FhuA for initiating internalization. Here, we provide what is to our knowledge the first structural evidence on the recognition mechanism, and our biochemical data show that another closely related lasso peptide cannot interact with FhuA. Our work provides an explanation on the narrow activity spectrum of lasso peptides and opens the path to the development of new antibacterials.

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Figure 1: Structure of E. coli FhuA in complex with MccJ25.
Figure 2: Interaction studies of lasso peptides with FhuA by phage T5 infection and non-denaturing MS.

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References

  1. 1

    Duquesne, S., Destoumieux-Garzon, D., Peduzzi, J. & Rebuffat, S. Nat. Prod. Rep. 24, 708–734 (2007).

    CAS  Article  Google Scholar 

  2. 2

    Rosengren, K.J. et al. J. Am. Chem. Soc. 125, 12464–12474 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Bayro, M.J. et al. J. Am. Chem. Soc. 125, 12382–12383 (2003).

    CAS  Article  Google Scholar 

  4. 4

    Delgado, M.A., Rintoul, M.R., Farias, R.N. & Salomon, R.A. J. Bacteriol. 183, 4543–4550 (2001).

    CAS  Article  Google Scholar 

  5. 5

    Salomón, R.A. & Farias, R.N. J. Bacteriol. 175, 7741–7742 (1993).

    Article  Google Scholar 

  6. 6

    Salomon, R.A. & Farias, R.N. J. Bacteriol. 177, 3323–3325 (1995).

    CAS  Article  Google Scholar 

  7. 7

    Destoumieux-Garzón, D. et al. Biochem. J. 389, 869–876 (2005).

    Article  Google Scholar 

  8. 8

    Ferguson, A.D. et al. Protein Sci. 9, 956–963 (2000).

    CAS  Article  Google Scholar 

  9. 9

    Ferguson, A.D. et al. Structure 9, 707–716 (2001).

    CAS  Article  Google Scholar 

  10. 10

    Ferguson, A.D., Hofmann, E., Coulton, J.W., Diederichs, K. & Welte, W. Science 282, 2215–2220 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Locher, K.P. et al. Cell 95, 771–778 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Killmann, H., Herrmann, C., Torun, A., Jung, G. & Braun, V. Microbiology 148, 3497–3509 (2002).

    CAS  Article  Google Scholar 

  13. 13

    Flayhan, A., Wien, F., Paternostre, M., Boulanger, P. & Breyton, C. Biochimie 94, 1982–1989 (2012).

    CAS  Article  Google Scholar 

  14. 14

    Housden, N.G. et al. Science 340, 1570–1574 (2013).

    CAS  Article  Google Scholar 

  15. 15

    Pugsley, A.P., Zimmerman, W. & Wehrli, W. J. Gen. Microbiol. 133, 3505–3511 (1987).

    CAS  PubMed  Google Scholar 

  16. 16

    Braun, M., Endriss, F., Killmann, H. & Braun, V. J. Bacteriol. 185, 5508–5518 (2003).

    CAS  Article  Google Scholar 

  17. 17

    Salomón, R.A. & Farias, R.N. J. Bacteriol. 174, 7428–7435 (1992).

    Article  Google Scholar 

  18. 18

    Knappe, T.A. et al. J. Am. Chem. Soc. 130, 11446–11454 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Kuznedelov, K. et al. J. Mol. Biol. 412, 842–848 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Cotter, P.D., Ross, R.P. & Hill, C. Nat. Rev. Microbiol. 11, 95–105 (2013).

    CAS  Article  Google Scholar 

  21. 21

    Pavlova, O., Mukhopadhyay, J., Sineva, E., Ebright, R.H. & Severinov, K. J. Biol. Chem. 283, 25589–25595 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Ducasse, R. et al. ChemBioChem 13, 371–380 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Lopez, F.E., Vincent, P.A., Zenoff, A.M., Salomon, R.A. & Farias, R.N. J. Antimicrob. Chemother. 59, 676–680 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Ferguson, A.D., Breed, J., Diederichs, K., Welte, W. & Coulton, J.W. Protein Sci. 7, 1636–1638 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Beis, K., Whitfield, C., Booth, I. & Naismith, J.H. Int. J. Biol. Macromol. 39, 10–14 (2006).

    CAS  Article  Google Scholar 

  26. 26

    Zirah, S. et al. J. Am. Soc. Mass Spectrom. 22, 467–479 (2011).

    CAS  Article  Google Scholar 

  27. 27

    Sobott, F., Hernandez, H., McCammon, M.G., Tito, M.A. & Robinson, C.V. Anal. Chem. 74, 1402–1407 (2002).

    CAS  Article  Google Scholar 

  28. 28

    Benesch, J.L. et al. Anal. Chem. 81, 1270–1274 (2009).

    CAS  Article  Google Scholar 

  29. 29

    Winter, G. J. Appl. Crystallogr. 43, 186–190 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Evans, P. Acta Crystallogr. D Biol. Crystallogr. 62, 72–82 (2006).

    Article  Google Scholar 

  31. 31

    McCoy, A.J. et al. J. Appl. Crystallogr. 40, 658–674 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Terwilliger, T.C. et al. Acta Crystallogr. D Biol. Crystallogr. 64, 61–69 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Blanc, E. et al. Acta Crystallogr. D Biol. Crystallogr. 60, 2210–2221 (2004).

    CAS  Article  Google Scholar 

  34. 34

    Langer, G., Cohen, S.X., Lamzin, V.S. & Perrakis, A. Nat. Protoc. 3, 1171–1179 (2008).

    CAS  Article  Google Scholar 

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Acknowledgements

We are grateful to P. Boulanger (Institute of Biochemistry and Molecular and Cellular Biophysics, Orsay University) for her kind gift of phage T5. We would like to thank the Diamond Light Source for beam time allocation and access. We thank the MS platform at the Muséum national d'Histoire naturelle for access to the spectrometers, together with K.-P. Yan and Z. Falk for contributing to the site-directed mutagenesis and phage competition experiments, respectively. The Oxford University Mass Spectrometry facility is funded by the Medical Research Council (DNRUBH0 to C.V.R.). M.P.L. is funded by the Wellcome Trust (WT/099165/Z/12/Z to S. Iwata). I.M. is supported by a Ministry of Science, Technology and Innovation postgraduate scholarship. Part of this work was supported by the Biotechnology and Biological Sciences Research Council (BB/H01778X/1 to K.B.).

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I.M. and S.Z. contributed equally to this work. S.R. and K.B. designed and managed the overall project. I.M. and K.B. grew crystals, collected data, and built and refined the structure. H.G.C. purified protein for ligand binding studies. All of the authors analyzed the structure. S.Z and Y.L. designed MccJ25 variants, and performed T5 competition and antibacterial assays. C.G. produced and purified peptides. S.M. and C.V.R. performed MS measurements and analysis. S.R. and K.B. wrote the manuscript with help from the other authors.

Corresponding authors

Correspondence to Sylvie Rebuffat or Konstantinos Beis.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1–5 and Supplementary Figures 1–12. (PDF 14897 kb)

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Mathavan, I., Zirah, S., Mehmood, S. et al. Structural basis for hijacking siderophore receptors by antimicrobial lasso peptides. Nat Chem Biol 10, 340–342 (2014). https://doi.org/10.1038/nchembio.1499

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