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TitleCryo-EM exposes diverse polymorphism in IAPP mutants to guide the rational design of peptide-based therapeutics.
Journal, issue, pagesJ Mol Biol, Vol. 437, Issue 21, Page 169405, Year 2025
Publish dateNov 1, 2025
AuthorsSaik Ann Ooi / Dylan Valli / Mikołaj I Kuska / Helena Marí / Himanshu Chaudhary / Weixiao Yuan Wahlgren / Sebastian Westenhoff / Alesia A Tietze / Anna Novials / Joan-Marc Servitja / Michał Maj /
PubMed AbstractIn 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 ...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.
External linksJ Mol Biol / PubMed:40850490
MethodsEM (helical sym.)
Resolution3.0 - 4.07 Å
Structure data

18441

8qj1

EMDB-18441, PDB-8qj1:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant A25P, polymorph 1
Method: EM (helical sym.) / Resolution: 3.06 Å

18671

8qvp

EMDB-18671, PDB-8qvp:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant S29P, polymorph 1
Method: EM (helical sym.) / Resolution: 3.75 Å

18672

8qvq

EMDB-18672, PDB-8qvq:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant S29P, polymorph 2
Method: EM (helical sym.) / Resolution: 4.07 Å

19353

8rm8

EMDB-19353, PDB-8rm8:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant S28P, polymorph 1
Method: EM (helical sym.) / Resolution: 3.0 Å

19354

8rm9

EMDB-19354, PDB-8rm9:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP) mutant S28P, polymorph 2
Method: EM (helical sym.) / Resolution: 4.06 Å

Source
  • homo sapiens (human)
KeywordsPROTEIN FIBRIL / amyloid

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