Structural Similarities and Differences between Amyloidogenic and Non-Amyloidogenic Islet Amyloid Polypeptide (IAPP) Sequences and Implications for the Dual Physiological and Pathological Activities of These Peptides

• DOI: 10.1371/journal.pcbi.1003211
• Publication Date: 2013-08-29T22:09:41Z
• Authors: Chun Wu; Joan-Emma Shea
• Keywords: Amyloid (mycology); Helix (gastropod); Sequence (biology); Amyloid disease; Coiled coil

IAPP, a 37 amino-acid peptide hormone belonging to the calcitonin family, is an intrinsically disordered protein that coexpressed and cosecreted along with insulin by pancreatic islet β-cells in response meals. IAPP plays physiological role glucose regulation; however, certain species, can aggregate this process linked β-cell death Type II Diabetes. Using replica exchange molecular dynamics extensive sampling (16 replicas per sequence 600 ns replica), we investigate structure of monomeric state two species aggregating peptides (human cat IAPP) non-aggregating (pig rat IAPP). Our simulations reveal pig conformations are very similar, consist helix-coil helix-hairpin conformations. The sequences, on other hand, populate same as sequence, but, addition, hairpin structure. exhaustive simulations, coupled available peptide-activity data, leads us structure-activity relationship (SAR) which propose functional carried out conformation, common both species. pathological may have multiple origins, including interaction helical elements membranes. Nonetheless, our suggest structure, only observed might be peptide, either direct precursor amyloid fibrils, or part cylindrin type toxic oligomer. We further fold also possible aggregation prone conformation would lead normally variants form fibrils under conditions where external perturbation applied. SAR used rational design therapeutics for treating diabetes.