The aggregation of the 37-residue polypeptide IAPP, as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of pancreatic β-islet cells in type II diabetes. While IAPP has been known to be the primary component of type II diabetes amyloid, the molecular interactions responsible for this aggregation have not been identified. To identify the aggregation-prone region(s), we constructed a library of randomly generated point mutants of IAPP. This mutant IAPP library was expressed in E. coli as genetic fusions to the reporter protein enhanced green fluorescent protein (EGFP). Because IAPP aggregates rapidly, both independently and when fused to EGFP, the fusion protein does not yield a functional, fluorescent EGFP. However, mutations of IAPP that result in non-amyloidogenic sequences remain soluble and allow EGFP to fold and fluoresce. Using this screen, we identified 22 single mutations, 4 double mutations and 2 triple mutations of IAPP that appear to be less amyloidogenic than wild type human IAPP. A comparison of these sequences suggests residues 13 and 15-17 comprise an additional aggregation-prone region outside of the main amyloidogenic region of IAPP.The aggregation of misfolded proteins into toxic oligomers and fibers has been linked to a variety of diseases such as type II diabetes, Alzheimer's disease and Parkinson's disease. In type II diabetes the amyloid-forming peptide is islet amyloid polypeptide (IAPP, amylin). This 37 amino acid polypeptide misfolds and forms aggregates within the pancreas. This misfolding into toxic aggregates, such as small soluble oligomers or large fibers, is believed to contribute to the loss of pancreatic β-cells. While the exact role of IAPP in type II diabetes is unclear, it is known that IAPP is found as extracellular deposits of amyloid in approximately 95% of patients afflicted with type II diabetes (1-3). IAPP has also been shown to be a toxic agent in vitro when added to human islet β-cells (4).Many of the therapeutic strategies for preventing or slowing the progression of amyloid diseases such as type II diabetes, involve slowing or preventing the aggregation of the amyloidogenic proteins. To this end, a great deal of effort has been made in identifying the amino acids responsible for the aggregation-prone nature of amyloidogenic peptides such as †