Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase

Karen S. Harris, Thomas Durek, Quentin Kaas, Aaron G. Poth, Edward K. Gilding, Brendon F. Conlan, Ivana Saska, Norelle L. Daly, Nicole L. van der Weerden, David J. Craik and Marilyn A. Anderson ()
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Karen S. Harris: La Trobe Institute for Molecular Science, La Trobe University
Thomas Durek: Institute for Molecular Bioscience, The University of Queensland
Quentin Kaas: Institute for Molecular Bioscience, The University of Queensland
Aaron G. Poth: Institute for Molecular Bioscience, The University of Queensland
Edward K. Gilding: Institute for Molecular Bioscience, The University of Queensland
Brendon F. Conlan: La Trobe Institute for Molecular Science, La Trobe University
Ivana Saska: Institute for Molecular Bioscience, The University of Queensland
Norelle L. Daly: Institute for Molecular Bioscience, The University of Queensland
Nicole L. van der Weerden: La Trobe Institute for Molecular Science, La Trobe University
David J. Craik: Institute for Molecular Bioscience, The University of Queensland
Marilyn A. Anderson: La Trobe Institute for Molecular Science, La Trobe University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Cyclotides are diverse plant backbone cyclized peptides that have attracted interest as pharmaceutical scaffolds, but fundamentals of their biosynthetic origin remain elusive. Backbone cyclization is a key enzyme-mediated step of cyclotide biosynthesis and confers a measure of stability on the resultant cyclotide. Furthermore, cyclization would be desirable for engineered peptides. Here we report the identification of four asparaginyl endopeptidases (AEPs), proteases implicated in cyclization, from the cyclotide-producing plant Oldenlandia affinis. We recombinantly express OaAEP1b and find it functions preferably as a cyclase by coupling C-terminal cleavage of propeptide substrates with backbone cyclization. Interestingly, OaAEP1b cannot cleave at the N-terminal site of O. affinis cyclotide precursors, implicating additional proteases in cyclotide biosynthesis. Finally, we demonstrate the broad utility of this enzyme by cyclization of peptides unrelated to cyclotides. We propose that recombinant OaAEP1b is a powerful tool for use in peptide engineering applications where increased stability of peptide products is desired.

Date: 2015
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DOI: 10.1038/ncomms10199

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