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Structural signatures of the class III lasso peptide BI-32169 and the branched-cyclic topoisomers using trapped ion mobility spectrometry–mass spectrometry and tandem mass spectrometry

  • Kevin Jeanne Dit Fouque
  • Vikash Bisram
  • Julian D. Hegemann
  • Séverine Zirah
  • Sylvie Rebuffat
  • Francisco Fernandez-LimaEmail author
Research Paper
Part of the following topical collections:
  1. Close-Up of Current Developments in Ion Mobility Spectrometry

Abstract

Lasso peptides are a class of bioactive ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by a mechanically interlocked topology, where the C-terminal tail of the peptide is threaded and trapped within an N-terminal macrolactam ring. BI-32169 is a class III lasso peptide containing one disulfide bond that further stabilizes the lasso structure. In contrast to its branched-cyclic analog, BI-32169 has higher stability and is known to exert a potent inhibitory activity against the human glucagon receptor. In the present work, tandem mass spectrometry, using collision-induced dissociation (CID) and electron capture dissociation (ECD), and trapped ion mobility spectrometry–mass spectrometry (TIMS-MS) experiments were carried out to evidence specific structural signatures of the two topologies. CID experiments showed similar fragmentation patterns for the two topoisomers, where a part of the C-terminal tail remains covalently linked to the macrolactam ring by the disulfide bond, which cannot clearly constitute a signature of the lasso topology. ECD experiments of BI-32169 showed an increase of hydrogen migration events in the loop region when compared with those of its branched-cyclic topoisomer evidencing specific structural signatures for the lasso topology. The high mobility resolving power of TIMS resulted in the identification of multiple conformations for the protonated species but did not allow the clear differentiation of the two topologies in mixture. When in complex with cesium metal ions, a reduced number of conformations led to a clear identification of the two structures. Experiments reducing and alkylating the disulfide bond of BI-32169 showed that the lasso structure is preserved and heat stable and the associated conformational changes provide new insights about the role of the disulfide bond in the inhibitory activity against the human glucagon receptor.

Graphical abstract

Keywords

BI-32169 Lasso topologies Branched-cyclic peptides Collision-induced dissociation Electron capture dissociation Trapped ion mobility spectrometry–mass spectrometry 

Notes

Author contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Funding information

This research received a financial support from the National Science Foundation Division of Chemistry, under CAREER award CHE-1654274, with co-funding from the Division of Molecular and Cellular Biosciences to FFL. J. D. H. received a financial support from the Deutsche Forschungsgemeinschaft (DFG Research Fellowship 309199717).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

216_2019_1613_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1239 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Kevin Jeanne Dit Fouque
    • 1
  • Vikash Bisram
    • 1
  • Julian D. Hegemann
    • 2
  • Séverine Zirah
    • 3
  • Sylvie Rebuffat
    • 3
  • Francisco Fernandez-Lima
    • 1
    • 4
    Email author
  1. 1.Department of Chemistry and BiochemistryFlorida International UniversityMiamiUSA
  2. 2.Department of ChemistryUniversity of Illinois at Urbana-ChampaignUrbanaUSA
  3. 3.Laboratory Molecules of Communication and Adaptation of MicroorganismsNational Museum of Natural HistoryParisFrance
  4. 4.Biomolecular Sciences InstituteFlorida International UniversityMiamiUSA

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