Folding transitions in calpain activator peptides studied by solution NMR spectroscopy

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Abstract

Calpastatin, the endogenous inhibitor of calpain, a cysteine protease in eukaryotic cells, is an intrinsically unstructured protein, which upon binding to the enzyme goes through a conformational change. Peptides calpA (SGKSGMDAALDDLIDTLGG) and calpC (SKPIGPDDAIDALSSDFTS), corresponding to the two conserved subdomains of calpastatin, are known to activate calpain and increase the Ca2+ sensitivity of the enzyme. Using solution NMR spectroscopy, here we show that calpA and calpC are disordered in water but assume an α-helical conformation in 50% CD3OH.The position and length of the helices are in agreement with those described in the literature for the bound state of the corresponding segments of calpastatin suggesting that the latter might be structurally primed for the interaction with its target. According to our data, the presence of Ca2+ induces a backbone rearrangement in the peptides, an effect thatmay contribute to setting the fine conformational balance required for the interaction of the peptides with calpain.

Original languageEnglish
Pages (from-to)404-410
Number of pages7
JournalJournal of Peptide Science
Volume15
Issue number6
DOIs
Publication statusPublished - Jul 13 2009

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Keywords

  • Calcium-binding
  • Calpain
  • Calpastatin
  • Conformational change
  • Folding
  • Inhibitor
  • Intrinsically unstructured proteins
  • NMR spectroscopy
  • Order-disorder transition

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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