Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies

Abdul Ghani, Hafiza, Henriques, Sonia Troeira, Huang, Yen-Hua, Swedberg, Joakim E. , Schroeder, Christina I. and Craik, David J. (2017) Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies. Biopolymers, 108 1: . doi:10.1002/bip.22927


Author Abdul Ghani, Hafiza
Henriques, Sonia Troeira
Huang, Yen-Hua
Swedberg, Joakim E.
Schroeder, Christina I.
Craik, David J.
Title Structural and functional characterization of chimeric cyclotides from the Möbius and trypsin inhibitor subfamilies
Journal name Biopolymers   Check publisher's open access policy
ISSN 1097-0282
0006-3525
Publication date 2017-01-01
Sub-type Article (original research)
DOI 10.1002/bip.22927
Open Access Status Not yet assessed
Volume 108
Issue 1
Total pages 11
Place of publication Hoboken, NJ, United States
Publisher John Wiley & Sons
Language eng
Abstract Cyclotides are plant-derived host defense peptides displaying exceptional stability due to their cyclic cystine knot comprising three intertwined disulfide bonds and a cyclic backbone. Their six conserved cysteine residues are separated by backbone loops with diverse sequences. Prototypical cyclotides from the Möbius (kalata B1) and trypsin inhibitor (MCoTI-II) subfamilies lack sequence homology with one another, but both are able to penetrate cells, apparently via different mechanisms. To delineate the influence of the sequences of the loops on the structure and cell internalization of these two cyclotide subfamilies, a series of Möbius/trypsin inhibitor loop-chimeras of kalata B1 and MCoTI-II were synthesized, and structurally and functionally characterized. NMR analysis showed that the structural fold of the majority of chimeric peptides was minimally affected by the loop substitutions. Substituting loops 3, 5, or 6 of MCoTI-II into the corresponding loops of kalata B1 attenuated its hemolytic and cytotoxic activities, and greatly reduced its cell-penetrating properties. On the other hand, replacing loops of MCoTI-II with the corresponding loops of kalata B1 did not introduce cytotoxicity into the chimeras. Loops 2, 3, and 4 of MCoTI-II were found to contribute little to cell-penetrating properties. Overall, this study provides valuable insights into the structural basis for the hemolytic, cytotoxic, and cell-penetrating properties of kalata B1 and MCoTI-II, which could be useful for future engineering of cyclotides to carry bioactive epitopes to intracellular targets.
Keyword Chimeras
Cyclic peptides
Cyclotides
Kalata B1
Structure
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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