Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores

Qin Cao, David R. Boyer, Michael R. Sawaya, Romany Abskharon, Lorena Saelices, Binh A. Nguyen, Jiahui Lu, Kevin A. Murray, Fouad Kandeel, David S. Eisenberg

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world’s population. To visualize disease-relevant hIAPP fibrils, we extracted amyloid fibrils from islet cells of a T2D donor and amplified their quantity by seeding synthetic hIAPP. Cryo-EM studies revealed four fibril polymorphic atomic structures. Their resemblance to four unseeded hIAPP fibrils varies from nearly identical (TW3) to non-existent (TW2). The diverse repertoire of hIAPP polymorphs appears to arise from three distinct protofilament cores entwined in different combinations. The structural distinctiveness of TW1, TW2 and TW4 suggests they may be faithful replications of the pathogenic seeds. If so, the structures determined here provide the most direct view yet of hIAPP amyloid fibrils formed during T2D.

Original languageEnglish (US)
Pages (from-to)724-730
Number of pages7
JournalNature Structural and Molecular Biology
Volume28
Issue number9
DOIs
StatePublished - Sep 2021

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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