Amino Acids

, Volume 49, Issue 1, pp 103–116 | Cite as

Natural structural diversity within a conserved cyclic peptide scaffold

  • Alysha G. Elliott
  • Bastian Franke
  • David A. Armstrong
  • David J. Craik
  • Joshua S. Mylne
  • K. Johan Rosengren
Original Article

Abstract

We recently isolated and described the evolutionary origin of a diverse class of small single-disulfide bonded peptides derived from Preproalbumin with SFTI-1 (PawS1) proteins in the seeds of flowering plants (Asteraceae). The founding member of the PawS derived peptide (PDP) family is the potent trypsin inhibitor SFTI-1 (sunflower trypsin inhibitor-1) from Helianthus annuus, the common sunflower. Here we provide additional structures and describe the structural diversity of this new class of small peptides, derived from solution NMR studies, in detail. We show that although most have a similar backbone framework with a single disulfide bond and in many cases a head-to-tail cyclized backbone, they all have their own characteristics in terms of projections of side-chains, flexibility and physiochemical properties, attributed to the variety of their sequences. Small cyclic and constrained peptides are popular as drug scaffolds in the pharmaceutical industry and our data highlight how amino acid side-chains can fine-tune conformations in these promising peptides.

Keywords

Sunflower trypsin inhibitor-1 (SFTI-1) PawS derived peptide (PDP) Cyclic peptide Solution NMR spectroscopy Peptide structure 

Abbreviations

SFTI-1

Sunflower trypsin inhibitor-1

PawS1

Preproalbumin with SFTI-1

PDP

PawS-derived peptide

AEP

Asparaginyl endopeptidase

TOCSY

Total correlation spectroscopy

NOESY

Nuclear overhauser effect spectroscopy

DQF-COSY

Double quantum filtered correlation spectroscopy

HSQC

Heteronuclear single quantum coherence spectroscopy

RP-HPLC

Reverse phase high performance liquid chromatography

ESI-MS

Electrospray ionization mass spectrometry

Supplementary material

726_2016_2333_MOESM1_ESM.pdf (836 kb)
Supplementary material 1 (PDF 837 kb)

References

  1. Bernath-Levin K, Nelson C, Elliott AG, Jayasena AS, Millar AH, Craik DJ, Mylne JS (2015) Peptide macrocyclization by a bifunctional endoprotease. Chem Biol 22:571–582. doi:10.1016/j.chembiol.2015.04.010 CrossRefPubMedGoogle Scholar
  2. Braunschweiler L, Ernst RR (1983) Coherence transfer by isotropic mixing: application to proton correlation spectroscopy. J Magn Reson 53:521–528Google Scholar
  3. Chan LY, Gunasekera S, Henriques ST, Worth NF, Le S-J, Clark RJ, Campbell JH, Craik DJ, Daly NL (2011) Engineering pro-angiogenic peptides using stable disulfide-rich cyclic scaffolds. Blood 118:6709–6717. doi:10.1182/blood-2011-06-359141 CrossRefPubMedGoogle Scholar
  4. Chen VB, Arendall WB III, Headd JJ, Keedy DA, Immormino RM, Kapral GJ, Murray LW, Richardson JS, Richardson DC (2010) MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D 66:12–21. doi:10.1107/S0907444909042073 CrossRefPubMedGoogle Scholar
  5. Craik DJ, Daly NL, Bond T, Waine C (1999) Plant cyclotides: a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J Mol Biol 294:1327–1336. doi:10.1006/jmbi.1999.3383 CrossRefPubMedGoogle Scholar
  6. Craik DJ, Cemazar M, Daly NL (2006) The cyclotides and related macrocyclic peptides as scaffolds in drug design. Curr Opin Drug Disc 9:251–260Google Scholar
  7. Craik DJ, Fairlie DP, Liras S, Price D (2013) The future of peptide-based drugs. Chem Biol Drug Des 81:136–147. doi:10.1111/cbdd.12055 CrossRefPubMedGoogle Scholar
  8. Dawson PE, Muir TW, Clark-Lewis I, Kent SB (1994) Synthesis of proteins by native chemical ligation. Science 266:776–779CrossRefPubMedGoogle Scholar
  9. de Veer SJ, Swedberg JE, Akcan M, Rosengren KJ, Brattsand M, Craik DJ, Harris JM (2015) Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition. Biochem J 469:243–253. doi:10.1042/BJ20150412 CrossRefPubMedGoogle Scholar
  10. Eccles C, Guntert P, Billeter M, Wüthrich K (1991) Efficient analysis of protein 2D NMR spectra using the software package EASY. J Biomol NMR 1:111–130CrossRefPubMedGoogle Scholar
  11. Elliott AG, Delay C, Liu H, Phua Z, Rosengren KJ, Benfield AH, Panero JL, Colgrave ML, Jayasena AS, Dunse KM, Anderson MA, Schilling EE, Ortiz-Barrientos D, Craik DJ, Mylne JS (2014) Evolutionary origins of a bioactive peptide buried within preproalbumin. Plant Cell 26:981–995. doi:10.1105/tpc.114.123620 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Gibbs AC, Kondejewski LH, Gronwald W, Nip AM, Hodges RS, Sykes BD, Wishart DS (1998) Unusual beta-sheet periodicity in small cyclic peptides. Nat Struct Biol 5:284–288CrossRefPubMedGoogle Scholar
  13. Griesinger C, Sørensen OW, Ernst RR (1987) Practical aspects of the E.COSY technique, measurement of scalar spin-spin coupling constants in peptides. J Magn Reson 75:474–492Google Scholar
  14. Güntert P, Mumenthaler C, Wüthrich K (1997) Torsion angle dynamics for NMR structure calculation with the new program DYANA. J Mol Biol 273:283–298. doi:10.1006/jmbi.1997.1284 CrossRefPubMedGoogle Scholar
  15. Harris KS, Durek T, Kaas Q, Poth AG, Gilding EK, Conlan BF, Saska I, Daly NL, van der Weerden NL, Craik DJ, Anderson MA (2015) Efficient backbone cyclization of linear peptides by a recombinant asparaginyl endopeptidase. Nat Commun 6:10199. doi:10.1038/ncomms10199 CrossRefPubMedPubMedCentralGoogle Scholar
  16. He F, Huang F, Wilson KA, Tan-Wilson A (2007) Protein storage vacuole acidification as a control of storage protein mobilization in soybeans. J Exp Biol 58:1059–1070. doi:10.1093/jxb/erl267 Google Scholar
  17. Hutchinson EG, Thornton JM (1996) PROMOTIF—a program to identify and analyze structural motifs in proteins. Protein Sci 5:212–220. doi:10.1002/pro.5560050204 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Jeener J, Meier BH, Bachmann P, Ernst RR (1979) Investigation of exchange processes by two-dimensional NMR spectroscopy. J Chem Phys 71:4546–4553CrossRefGoogle Scholar
  19. Kessler H, Gehrke M, Lautz J, Kock M, Seebach D, Thaler A (1990) Complexation and medium effects on the conformation of cyclosporin A studied by NMR spectroscopy and molecular dynamics calculations. Biochem Pharmacol 40:169–173CrossRefPubMedGoogle Scholar
  20. Koradi R, Billeter M, Wüthrich K (1996) MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph 14:29–32CrossRefGoogle Scholar
  21. Korsinczky ML, Schirra HJ, Rosengren KJ, West J, Condie BA, Otvos L, Anderson MA, Craik DJ (2001) Solution structures by 1H NMR of the novel cyclic trypsin inhibitor SFTI-1 from sunflower seeds and an acyclic permutant. J Mol Biol 311:579–591. doi:10.1006/jmbi.2001.4887 CrossRefPubMedGoogle Scholar
  22. Korsinczky ML, Clark RJ, Craik DJ (2005) Disulfide bond mutagenesis and the structure and function of the head-to-tail macrocyclic trypsin inhibitor SFTI-1. Biochemistry 44:1145–1153. doi:10.1021/bi048297r CrossRefPubMedGoogle Scholar
  23. Luckett S, Garcia RS, Barker JJ, Konarev AV, Shewry PR, Clarke AR, Brady RL (1999) High-resolution structure of a potent, cyclic proteinase inhibitor from sunflower seeds. J Mol Biol 290:525–533. doi:10.1006/jmbi.1999.2891 CrossRefPubMedGoogle Scholar
  24. Mylne JS, Colgrave ML, Daly NL, Chanson AH, Elliott AG, McCallum EJ, Jones A, Craik DJ (2011) Albumins and their processing machinery are hijacked for cyclic peptides in sunflower. Nat Chem Biol 7:257–259. doi:10.1038/nchembio.542 CrossRefPubMedGoogle Scholar
  25. Mylne JS, Chan LY, Chanson AH, Daly NL, Schaefer H, Bailey TL, Nguyencong P, Cascales L, Craik DJ (2012) Cyclic peptides arising by evolutionary parallelism via asparaginyl-endopeptidase-mediated biosynthesis. Plant Cell 24:2765–2778. doi:10.1105/tpc.112.099085 CrossRefPubMedPubMedCentralGoogle Scholar
  26. Nguyen GK, Wang S, Qiu Y, Hemu X, Lian Y, Tam JP (2014) Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis. Nat Chem Biol 10:732–738. doi:10.1038/nchembio.1586 CrossRefPubMedGoogle Scholar
  27. Otegui MS, Herder R, Schulze J, Jung R, Staehelin LA (2006) The proteolytic processing of seed storage proteins in Arabidopsis embryo cells starts in the multivesicular bodies. Plant Cell 18:2567–2581. doi:10.1105/tpc.106.040931 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Rance M, Sørensen OW, Bodenhausen G, Wagner G, Ernst RR, Wüthrich K (1983) Improved spectral resolution in COSY 1H NMR spectra of proteins via double quantum filtering. Biochem Biophys Res Commun 117:479–485CrossRefPubMedGoogle Scholar
  29. Schmidt B, Hogg PJ (2007) Search for allosteric disulfide bonds in NMR structures. BMC Struct Biol 7:49. doi:10.1186/1472-6807-7-49 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Schmidt B, Ho L, Hogg PJ (2006) Allosteric disulfide bonds. Biochemistry 45:7429–7433. doi:10.1021/bi0603064 CrossRefPubMedGoogle Scholar
  31. Schnölzer M, Alewood P, Jones A, Alewood D, Kent SBH (1992) In situ neutralization in Boc-chemistry solid phase peptide synthesis. Int J Pept Protein Res 40:180–193CrossRefPubMedGoogle Scholar
  32. Shen Y, Delaglio F, Cornilescu G, Bax A (2009) TALOS + : a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts. J Biomol NMR 44:213–223. doi:10.1007/s10858-009-9333-z CrossRefPubMedPubMedCentralGoogle Scholar
  33. Swedberg JE, Nigon LV, Reid JC, de Veer SJ, Walpole CM, Stephens CR, Walsh TP, Takayama TK, Hooper JD, Clements JA, Buckle AM, Harris JM (2009) Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chem Biol 16:633–643. doi:10.1016/j.chembiol.2009.05.008 CrossRefPubMedGoogle Scholar
  34. Taiz L (1992) The Plant Vacuole. J Exp Biol 172:113–122PubMedGoogle Scholar
  35. Tyndall JDA, Nall T, Fairlie DP (2005) Proteases universally recognize beta strands in their active sites. Chem Rev 105:973–1000. doi:10.1021/cr040669e CrossRefPubMedGoogle Scholar
  36. Wishart DS, Case DA (2002) Use of chemical shifts in macromolecular structure determination. Method Enzymol 338:3–34. doi:10.1016/S0076-6879(02)38214-4 CrossRefGoogle Scholar
  37. Wishart DS, Bigam CG, Holm A, Hodges RS, Sykes BD (1995) 1H, 13C and 15N random coil NMR chemical shifts of the common amino acids. I. Investigations of nearest-neighbor effects. J Biomol NMR 5:67–81CrossRefPubMedGoogle Scholar
  38. Wüthrich K (1986) NMR of proteins and nucleic acids. Wiley-Interscience, New YorkGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Alysha G. Elliott
    • 1
  • Bastian Franke
    • 2
  • David A. Armstrong
    • 2
  • David J. Craik
    • 1
  • Joshua S. Mylne
    • 1
    • 3
  • K. Johan Rosengren
    • 1
    • 2
  1. 1.Institute for Molecular BioscienceThe University of QueenslandBrisbaneAustralia
  2. 2.School of Biomedical SciencesThe University of QueenslandBrisbaneAustralia
  3. 3.School of Chemistry and Biochemistry and ARC Centre of Excellence in Plant Energy BiologyThe University of Western AustraliaCrawley, PerthAustralia

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