Cryo-EM exposes diverse polymorphism in IAPP mutants to guide the rational design of peptide-based therapeutics.

Ooi SA, Valli D, Kuska MI, Marí H, Chaudhary H, Wahlgren WY, Westenhoff S, Tietze AA, Novials A, Servitja JM, Maj M

J. Mol. Biol. 437 (21) 169405 [2025-11-01; online 2025-08-22]

In the pursuit of potential therapeutic agents for type 2 diabetes, non-amyloidogenic forms of the human Islet Amyloid Polypeptide (hIAPP) containing site-specific mutations are of significant interest. In the present study, we dissect the three proline mutations present in the core region of the non-amyloidogenic rat IAPP into single-point mutations at A25P, S28P, and S29P sites. We apply high-resolution cryo-electron microscopy and solve the structures of 6 polymorphs formed by these mutants, revealing the peptide's self-assembly patterns and identifying critical interactions that reinforce these structures in the presence of the β-sheet breaker. A unique trimeric aggregate with C3 symmetry was identified in the A25P mutant, which we resolved with a 3.05 Å resolution, while asymmetric trimeric assemblies were observed in the other mutants. Guided by the high-resolution structural models of A25P and S28P fibrils obtained in our study, we successfully designed novel non-amyloidogenic mutants of IAPP with potential therapeutic value. Our findings demonstrate the immense potential of structure-based approaches in developing effective therapeutics against amyloid diseases.

Integrated Microscopy Technologies Gothenburg [Service]

PubMed 40850490

DOI 10.1016/j.jmb.2025.169405

Crossref 10.1016/j.jmb.2025.169405

pii: S0022-2836(25)00471-1