The Single Disulfide-Directed β-Hairpin Fold. Dynamics, Stability, and Engineering

Biochemistry. 2017 May 16;56(19):2455-2466. doi: 10.1021/acs.biochem.7b00120. Epub 2017 May 2.

Abstract

Grafting bioactive peptide sequences onto small cysteine-rich scaffolds is a promising strategy for enhancing their stability and value as novel peptide-based therapeutics. However, correctly folded disulfide-rich peptides can be challenging to produce by either recombinant or synthetic means. The single disulfide-directed β-hairpin (SDH) fold, first observed in contryphan-Vc1, provides a potential alternative to complex disulfide-rich scaffolds. We have undertaken recombinant production of full-length contryphan-Vc1 (rCon-Vc1[Z1Q]) and a truncated analogue (rCon-Vc11-22[Z1Q]), analyzed the backbone dynamics of rCon-Vc1[Z1Q], and probed the conformational and proteolytic stability of these peptides to evaluate the potential of contryphan-Vc1 as a molecular scaffold. Backbone 15N relaxation measurements for rCon-Vc1[Z1Q] indicate that the N-terminal domain of the peptide is ordered up to Thr19, whereas the remainder of the C-terminal region is highly flexible. The solution structure of truncated rCon-Vc11-22[Z1Q] was similar to that of the full-length peptide, indicating that the flexible C-terminus does not have any effect on the structured domain of the peptide. Contryphan-Vc1 exhibited excellent proteolytic stability against trypsin and chymotrypsin but was susceptible to pepsin digestion. We have investigated whether contryphan-Vc1 can accept a bioactive epitope while maintaining the structure of the peptide by introducing peptide sequences based on the DINNN motif of inducible nitric oxide synthase. We show that sCon-Vc11-22[NNN12-14] binds to the iNOS-binding protein SPSB2 with an affinity of 1.3 μM while maintaining the SDH fold. This study serves as a starting point in utilizing the SDH fold as a peptide scaffold.

Publication types

  • Comparative Study

MeSH terms

  • Conotoxins / chemistry*
  • Conotoxins / genetics
  • Conotoxins / metabolism
  • Cysteine / chemistry
  • Cystine / chemistry
  • Epitopes
  • Humans
  • Kinetics
  • Nitrogen Isotopes
  • Oxidation-Reduction
  • Peptide Fragments / chemistry
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / genetics
  • Peptides, Cyclic / metabolism
  • Protein Conformation, beta-Strand
  • Protein Engineering*
  • Protein Folding
  • Protein Stability
  • Proteolysis
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Solubility
  • Suppressor of Cytokine Signaling Proteins / chemistry*
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Surface Plasmon Resonance

Substances

  • Conotoxins
  • Epitopes
  • Nitrogen Isotopes
  • Peptide Fragments
  • Peptides, Cyclic
  • Recombinant Fusion Proteins
  • Recombinant Proteins
  • SPSB2 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • contryphan
  • Cystine
  • alpha-conotoxin Vc1.1
  • Cysteine