Steen Vang Petersen

The three-dimensional structure of an H-superfamily conotoxin reveals a granulin fold arising from a common ICK cysteine framework

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Lau D. Nielsen, University of Copenhagen
  • ,
  • Mads M. Foged, University of Copenhagen
  • ,
  • Anastasia Albert, Norut Northern Research Institute
  • ,
  • Andreas B. Bertelsen, University of Copenhagen
  • ,
  • Cecilie L. Søltoft, University of Copenhagen
  • ,
  • Samuel D. Robinson, University of Utah, Monash University
  • ,
  • Steen V. Petersen
  • Anthony W. Purcell, Monash University
  • ,
  • Baldomero M. Olivera, University of Utah
  • ,
  • Raymond S. Norton, Monash University
  • ,
  • Terje Vasskog, Norut Northern Research Institute
  • ,
  • Helena Safavi-Hemami, University of Copenhagen, University of Utah
  • ,
  • Kaare Teilum, University of Copenhagen
  • ,
  • Lars Ellgaard, University of Copenhagen

Venomous marine cone snails produce peptide toxins (conotoxins) that bind ion channels and receptors with high specificity and therefore are important pharmacological tools. Conotoxins contain conserved cysteine residues that form disulfide bonds that stabilize their structures. To gain structural insight into the large, yet poorly characterized conotoxin H-superfamily, we used NMR and CD spectroscopy along with MS-based analyses to investigate H-Vc7.2 from Conus victoriae, a peptide with a VI/VII cysteine framework. This framework has CysI-CysIV/CysII-CysV/CysIII-CysVI connectivities, which have invariably been associated with the inhibitor cystine knot (ICK) fold. However, the solution structure of recombinantly expressed and purified H-Vc7.2 revealed that although it displays the expected cysteine connectivities, H-Vc7.2 adopts a different fold consisting of two stacked -hairpins with opposing -strands connected by two parallel disulfide bonds, a structure homologous to the N-terminal region of the human granulin protein. Using structural comparisons, we subsequently identified several toxins and nontoxin proteins with this “mini-granulin” fold. These findings raise fundamental questions concerning sequence-structure relationships within peptides and proteins and the key determinants that specify a given fold.

Original languageEnglish
JournalJournal of Biological Chemistry
Pages (from-to)8745-8759
Number of pages15
Publication statusPublished - 2019

Bibliographical note

© 2019 Nielsen et al.

    Research areas

  • -hairpin, 2 BETA-HAIRPINS, CD spectroscopy, CHEMICAL-SHIFTS, COEFFICIENTS, CYSTINE KNOT, FAMILY, NMR spectroscopy, PHASE, PROTEIN, STACK, THERAPEUTICS, VENOM PEPTIDES, antistasin, conotoxin, disulfide, disulfide bond, granulin, inhibitor cystine knot, protein conformation, protein evolution, protein expression, protein structure, protein-disulfide isomerase, toxin, Conotoxins/chemistry, Protein Stability, Mollusk Venoms/metabolism, Cysteine/chemistry, Amino Acid Sequence, Magnetic Resonance Spectroscopy, Disulfides/chemistry, Recombinant Proteins/biosynthesis, Protein Folding, Animals, Conus Snail/metabolism, Protein Conformation, beta-Strand, Granulins/chemistry

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