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Structural mapping of oligomeric intermediates in an amyloid assembly pathway

Karamanos, Theodoros K., Jackson, Matthew P., Calabrese, Antonio N., Goodchild, Sophia C., Cawood, Emma E.C., Thompson, Gary S., Kalverda, Arnout P., Hewitt, Eric W., Radford, Sheena E. (2019) Structural mapping of oligomeric intermediates in an amyloid assembly pathway. eLife, 8 . E-ISSN 2050-084X. (doi:10.7554/eLife.46574.001) (KAR id:77475)

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https://dx.doi.org/10.7554/eLife.46574.001

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.

Item Type: Article
DOI/Identification number: 10.7554/eLife.46574.001
Subjects: Q Science > QP Physiology (Living systems) > QP506 Molecular biology
Divisions: Faculties > Sciences > School of Biosciences
Depositing User: Gary Thompson
Date Deposited: 15 Oct 2019 14:03 UTC
Last Modified: 16 Oct 2019 10:56 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/77475 (The current URI for this page, for reference purposes)
Karamanos, Theodoros K.: https://orcid.org/0000-0003-2297-540X
Calabrese, Antonio N.: https://orcid.org/0000-0003-2437-7761
Cawood, Emma E.C.: https://orcid.org/0000-0002-2707-8022
Thompson, Gary S.: https://orcid.org/0000-0001-9399-7636
Hewitt, Eric W.: https://orcid.org/0000-0002-6238-6303
Radford, Sheena E.: https://orcid.org/0000-0002-3079-8039
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