Structural mapping of oligomeric intermediates in an amyloid assembly pathway

Theodoros K. Karamanos, Matthew P. Jackson, Antonio N. Calabrese, Sophia C. Goodchild, Emma E. Cawood, Gary S. Thompson, Arnout P. Kalverda, Eric W. Hewitt, Sheena E. Radford*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Transient oligomers are commonly formed in the early stages of amyloid assembly. Determining the structure(s) of these species and defining their role(s) in assembly is key to devising new routes to control disease. Here, using a combination of chemical kinetics, NMR spectroscopy and other biophysical methods, we identify and structurally characterize the oligomers required for amyloid assembly of the protein ΔN6, a truncation variant of human β2-microglobulin (β2m) found in amyloid deposits in the joints of patients with dialysis-related amyloidosis. The results reveal an assembly pathway which is initiated by the formation of head-to-head non-toxic dimers and hexamers en route to amyloid fibrils. Comparison with inhibitory dimers shows that precise subunit organization determines amyloid assembly, while dynamics in the C-terminal strand hint to the initiation of cross-β structure formation. The results provide a detailed structural view of early amyloid assembly involving structured species that are not cytotoxic.

Original languageEnglish
Article numbere46574
JournaleLife
Volume8
DOIs
Publication statusPublished - 25 Sep 2019
Externally publishedYes

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  • Cite this

    Karamanos, T. K., Jackson, M. P., Calabrese, A. N., Goodchild, S. C., Cawood, E. E., Thompson, G. S., ... Radford, S. E. (2019). Structural mapping of oligomeric intermediates in an amyloid assembly pathway. eLife, 8, [e46574]. https://doi.org/10.7554/eLife.46574.001