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Cystine Knot Folding in Cyclotides

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Folding of Disulfide Proteins

Part of the book series: Protein Reviews ((PRON,volume 14))

Abstract

Cyclotides are naturally occurring plant-based proteins of approximately 30 amino acids in size that contain a head-to-tail cyclized backbone and a cystine knot motif formed by their three conserved disulfide bonds. Their exceptional stability and unique topology make them valuable frameworks in drug design or protein engineering applications. To facilitate such applications and to explore structure–activity relationships of cyclotides it is useful to be able to chemically synthesize them, a process that is readily achieved via solid phase peptide synthesis followed by oxidative folding. This chapter describes what is known about the oxidative folding of cyclotides, both in chemical folding buffers and assisted by a protein disulfide isomerase enzyme isolated from a cyclotide-producing plant. Formation of the cystine knot motif is readily achieved, despite its apparent topological complexity.

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Acknowledgments

Work in DC’s laboratory on cyclotides is supported by grants from the Australian Research Council (ARC) and the National Health and Medical Research Council (NHMRC). NLD is a Queensland Smart State Fellow and DJC is an NHMRC Principal Research Fellow. UG is supported by grants from the Swedish Research Council (VR) and the Swedish Foundation for Strategic Research (SSF).

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Authors and Affiliations

  1. Institute for Molecular Bioscience, Division of Chemistry and Structural Biology, The University of Queensland, QLD, 4072, Brisbane, Australia

    Norelle L. Daly & David J. Craik

  2. Center for Physiology and Pharmacology, University of Vienna, A-1090, Vienna, Austria

    Christian W. Gruber

  3. Division of Pharmacognosy, Department of Medicinal Chemistry, Uppsala University, Biomedical Centre, 574, SE-751 23, Uppsala, Sweden

    Ulf Göransson

Authors
  1. Norelle L. Daly
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  2. Christian W. Gruber
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  3. Ulf Göransson
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  4. David J. Craik
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Corresponding author

Correspondence to David J. Craik .

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Editors and Affiliations

  1. Brown Foundation Inst. of Molecular Medi, The University of Texas, Houston, 77030, Texas, USA

    Rowen J. Y. Chang

  2. Institut de Biotecnologia i de Biomed., Dept. de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, 08193, Spain

    Salvador Ventura

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Daly, N.L., Gruber, C.W., Göransson, U., Craik, D.J. (2011). Cystine Knot Folding in Cyclotides. In: Chang, R., Ventura, S. (eds) Folding of Disulfide Proteins. Protein Reviews, vol 14. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7273-6_3

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