Identification of transmissible proteotoxic oligomer-like fibrils that expand conformational diversity of amyloid assemblies
| Autor: | Mathew Sebastiao, Steve Bourgault, Alexandre A. Arnold, Ximena Zottig, Isabelle Marcotte, Phuong Trang Nguyen |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Amyloid QH301-705.5 Medicine (miscellaneous) Fibril Oligomer General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biophysical chemistry mental disorders Benzothiazoles Biology (General) 030304 developmental biology 0303 health sciences Cell Death Chemistry Type 2 diabetes Amyloidosis Amyloid fibril Islet Amyloid Polypeptide High surface Amyloid deposition Diabetes Mellitus Type 2 Biophysics Protein folding General Agricultural and Biological Sciences Hydrophobic and Hydrophilic Interactions 030217 neurology & neurosurgery |
| Zdroj: | Communications Biology Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2399-3642 |
| Popis: | Protein misfolding and amyloid deposition are associated with numerous diseases. The detailed characterization of the proteospecies mediating cell death remains elusive owing to the (supra)structural polymorphism and transient nature of the assemblies populating the amyloid pathway. Here we describe the identification of toxic amyloid fibrils with oligomer-like characteristics, which were assembled from an islet amyloid polypeptide (IAPP) derivative containing an Asn-to-Gln substitution (N21Q). While N21Q filaments share structural properties with cytocompatible fibrils, including the 4.7 Å inter-strand distance and β-sheet-rich conformation, they concurrently display characteristics of oligomers, such as low thioflavin-T binding, high surface hydrophobicity and recognition by the A11 antibody, leading to high potency to disrupt membranes and cause cellular dysfunction. The toxic oligomer-like conformation of N21Q fibrils, which is preserved upon elongation, is transmissible to naïve IAPP. These stable fibrils expanding the conformational diversity of amyloid assemblies represent an opportunity to elucidate the structural basis of amyloid disorders. Nguyen et al identified cytotoxic amyloid fibrils with oligomer-like characteristics, which were assembled from an islet amyloid polypeptide (IAPP) derivative containing an Asn-to-Gln substitution (N21Q). They presented evidence to show that these stable fibrils expand the conformational diversity of amyloid assemblies, which represents an opportunity to elucidate the structural basis of amyloid disorders. |
| Databáze: | OpenAIRE |
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