Limited solubility and precipitation of amyloidogenic sequences like the Alzheimer peptide (b-AP) is a major obstacle to a molecular understanding of protein fibrillation and deposition processes. We have circumvented the solubility problem by engineering parts of the b-AP sequence into a soluble scaffold, the monomeric protein S6. The S6 construct crystallizes as a tetramer which is linked by the b-AP residues forming intermolecular anti-parallel b-sheets. The construct also shows increased levels of coil aggregation during refolding, the extent of which correlates with the degree of b-AP homology in its sequence. A 15-mer peptide encompassing the engineered sequence forms fibrils, unlike the peptide corresponding to wildtype S6. Mutational analysis of the aggregation process implies the existence of "structural gatekeepers" in the wildtype protein, that is, charged amino acid residues which prevent aggregation by interrupting contiguous stretches of hydrophobic residues in the primary sequence.