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Structural evolution of fibril polymorphs during amyloid assembly.

Wilkinson M, Xu Y, Thacker D, Taylor AIP, Fisher DG, Gallardo RU, Radford SE, Ranson NA
Cell 186 5798-5811.e26 (2023)
Related entries: 8awt, 8az0, 8az1, 8az3, 8az4, 8az5, 8az6, 8az7

Cited: 3 times
EuropePMC logo PMID: 38134875

Abstract

Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.

Articles citing this publication (3)

  1. Residues 2 to 7 of α-synuclein regulate amyloid formation via lipid-dependent and lipid-independent pathways. Dewison KM, Rowlinson B, Machin JM, Crossley JA, Thacker D, Wilkinson M, Ulamec SM, Khan GN, Ranson NA, van Oosten-Hawle P, Brockwell DJ, Radford SE. Proc Natl Acad Sci U S A 121 e2315006121 (2024)
  2. A Targetable N-Terminal Motif Orchestrates α-Synuclein Oligomer-to-Fibril Conversion. Santos J, Cuellar J, Pallarès I, Byrd EJ, Lends A, Moro F, Abdul-Shukkoor MB, Pujols J, Velasco-Carneros L, Sobott F, Otzen DE, Calabrese AN, Muga A, Pedersen JS, Loquet A, Valpuesta JM, Radford SE, Ventura S. J Am Chem Soc 146 12702-12711 (2024)
  3. Three-dimensional architecture of ESCRT-III flat spirals on the membrane. Liu M, Liu Y, Song T, Yang L, Qi L, Zhang YZ, Wang Y, Shen QT. Proc Natl Acad Sci U S A 121 e2319115121 (2024)


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