Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

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DOI

  • Daniel E. Otzen
  • Ole Kristensen, Department of Molecular Biophysics, Lunds Universitet, University of Copenhagen, Denmark
  • Mikael Oliveberg, Clinical Sciences, Umea universitet, Klinisk vetenskap.

Limited solubility and precipitation of amyloidogenic sequences such as the Alzheimer peptide (β-AP) are major obstacles to a molecular understanding of protein fibrillation and deposition processes. Here we have circumvented the solubility problem by stepwise engineering a β-AP homology into a soluble scaffold, the monomeric protein S6. The S6 construct with the highest β-AP homology crystallizes as a tetramer that is linked by the β-AP residues forming intermolecular antiparallel β-sheets. This construct also shows increased coil aggregation during refolding, and a 14-mer peptide encompassing the engineered sequence forms fibrils. Mutational analysis shows that intermolecular association is linked to the overall hydrophobicity of the sticky sequence and implies the existence of 'structural gatekeepers' in the wild-type protein, that is, charged side chains that prevent aggregation by interrupting contiguous stretches of hydrophobic residues in the primary sequence.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue18
Pages (from-to)9907-9912
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 29 Aug 2000

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