Amyloidogenicity of recombinant human pro-islet amyloid polypeptide (ProIAPP)

Monika Krampert, Jürgen Bernhagen, Jürgen Schmucker, Anita Horn, Anke Schmauder, Herwig Brunner, Wolfgang Voelter, Aphrodite Kapurniotu

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40 Scopus citations


Background: Pancreatic amyloid has been associated with type II diabetes. The major constituent of pancreatic amyloid is the 37-residue peptide islet amyloid polypeptide (IAPP). IAPP is expressed as a 67-residue pro-peptide called ProIAPP which is processed to IAPP following stimulation. While the molecular events underlying IAPP amyloid formation in vitro have been studied, little is known about the role of ProIAPP in the formation of pancreatic amyloid. This has been due in part to the limited availability of purified ProIAPP for conformational and biochemical studies. Results: We present a method for efficient recombinant expression and purification of ProIAPP and a processing site mutant, mutProIAPP, as thioredoxin (Trx) fusion proteins. Conformation and amyloidogenicity of cleaved ProIAPP and mutProIAPP and the fusion proteins were assessed by circular dichroism, electron microscopy and Congo red staining. We find that ProIAPP and mutProIAPP exhibit strong self-association potentials and are capable of forming amyloid. However, the conformational transitions of ProIAPP and mutProIAPP during aging and amyloidogenesis are distinct from the random coil-to-β-sheet transition of IAPP. Both proteins are found to be less amyloidogenic than IAPP and besides fibrils a number of non-fibrillar but ordered aggregates form during aging of ProIAPP. ProIAPP aggregates are cytotoxic on pancreatic cells but less cytotoxic than IAPP while mutProIAPP aggregates essentially lack cytotoxicity. The Trx fusion proteins are neither amyloidogenic nor cytotoxic. Conclusions: Our studies suggest that ProIAPP has typical properties of an amyloidogenic polypeptide but also indicate that the pro-region suppresses the amyloidogenic and cytotoxic potentials of IAPP.

Original languageEnglish
Pages (from-to)855-871
Number of pages17
JournalChemistry and Biology
Issue number11
StatePublished - 2000
Externally publishedYes


  • Aggregation
  • Amyloidogenicity
  • Cytotoxicity
  • Islet amyloid polypeptide
  • Pro-islet amyloid polypeptide


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