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

• Published in: Nature structural & molecular biology Vol. 28; no. 9; pp. 724 - 730
• Main Authors: Cao, Qin, Boyer, David R., Sawaya, Michael R., Abskharon, Romany, Saelices, Lorena, Nguyen, Binh A., Lu, Jiahui, Murray, Kevin A., Kandeel, Fouad, Eisenberg, David S.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2021; Nature Publishing Group
• Subjects: 101/28; 631/337/470/2284; 631/535/1258/1259; 82/1; Amino Acid Sequence; Amylin; Amyloid; Amyloid - chemistry; Amyloid - isolation & purification; Amyloidosis; Analysis; Biochemistry; Biological Microscopy; Biomedical and Life Sciences; Congo Red; Cores; Cryoelectron Microscopy; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - metabolism; Evaluation; Fibrils; Genetic aspects; Genetic polymorphisms; Genotype; Humans; Islet Amyloid Polypeptide - chemistry; Islet Amyloid Polypeptide - genetics; Islet cells; Islets of Langerhans - chemistry; Life Sciences; Membrane Biology; Models, Molecular; Polymerase Chain Reaction; Polypeptides; Protein Aggregates; Protein Conformation; Protein Structure; Recombinant Proteins - chemistry; Seeds; Sequence Analysis, DNA; Staining and Labeling; United States
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/s41594-021-00646-x

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. Human islet amyloid polypeptide (hIAPP) is a protein commonly forming aggregates in islet cells of those afflicted by type II diabetes. New structures of fibrils seeded with patient-derived material reveal a diverse repertoire of structures, some of which may resemble those appearing in vivo.