Cryo-EM exposes diverse polymorphism in IAPP mutants to guide the rational design of peptide-based therapeutics
Year: 2025
Type: article
Abstract: 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.
Source: Journal of Molecular Biology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,730
Funders: Kempe Foundation, European Commission, European Foundation for the Study of Diabetes, Svenska Sällskapet för Medicinsk Forskning, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Göteborgs Universitet, Uppsala Universitet, Kempestiftelserna, Stockholms Universitet, Science for Life Laboratory, Harald och Greta Jeanssons Stiftelse, Instituto de Salud Carlos III
Awards: G116878258, G1616192813, G1982491442, G2252777492, Comunicación entre órganos y diabetes tipo 2: efectos de exosomas circulantes sobre los islotes pancreáticos, G3672930514, G398157425, PReSTO - processing and software for Integrative Structural Biology, G4410145247, G4760700283, National Microscopy Infrastructure, G4919463464, G4934101106, G5000462918, G5601842732, G576672233, G712881263, G7569742080, Towards molecular understanding of type 2 diabetes – Resolving the structure and dynamics of the cytotoxic intermediate of the human Islet Amyloid Polypeptide, G8417133636, NAISS
OpenAlex ID: W4413422747