High-resolution structure of proIAPP(1-48) fibrils suggests a mechanistic pathway for diabetes-associated IAPP fibril polymorphs.

ABSTRACT: The human islet amyloid polypeptide (hIAPP) aggregates into amyloid fibrils that contribute to β-cell failure in type 2 diabetes. hIAPP is produced from a 67-residue precursor, proIAPP, but incomplete cleavage by prohormone convertase 2 (PC2) produces the 48-residue intermediate proIAPP(1-48), which accelerates amyloid formation in vivo. Here we show that proIAPP(1-48) assembles almost exclusively into a single fibril polymorph. Using cryo-electron microscopy we solved its structure at 3.5 Å resolution and uncovered a P-shaped, C2-symmetric dimer whose backbone and side-chain packing are nearly identical to the disease-associated TW2 polymorph propagated from pancreatic tissue, although with different helical symmetry. All eleven extra N-terminal residues remain disordered but creat

SUBMITTER: Valli D 

PROVIDER: S-EPMC12590159 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature