Issue 7, 2017

Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers

Abstract

Although amyloid assembly in vitro is commonly investigated using single protein sequences, fibril formation in vivo can be more heterogeneous, involving co-assembly of proteins of different length, sequence and/or post-translational modifications. Emerging evidence suggests that co-polymerization can alter the rate and/or mechanism of aggregation and can contribute to pathogenicity. Electrospray ionization-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS) is uniquely suited to the study of these heterogeneous ensembles. Here, ESI-IMS-MS combined with analysis of fibrillation rates using thioflavin T (ThT) fluorescence, is used to track the course of aggregation of variants of islet-amyloid polypeptide (IAPP) in isolation and in pairwise mixtures. We identify a sub-population of extended monomers as the key precursors of amyloid assembly, and reveal that the fastest aggregating sequence in peptide mixtures determines the lag time of fibrillation, despite being unable to cross-seed polymerization. The results demonstrate that co-polymerization of IAPP sequences radically alters the rate of amyloid assembly by altering the conformational properties of the mixed oligomers that form.

Graphical abstract: Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers

Supplementary files

Article information

Article type
Edge Article
Submitted
09 Feb 2017
Accepted
03 Mai 2017
First published
09 Mai 2017
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2017,8, 5030-5040

Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers

L. M. Young, L. Tu, D. P. Raleigh, A. E. Ashcroft and S. E. Radford, Chem. Sci., 2017, 8, 5030 DOI: 10.1039/C7SC00620A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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