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Issue 7, 2017
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Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers

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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

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Publication details

The article was received on 09 Feb 2017, accepted on 03 May 2017 and first published on 09 May 2017


Article type: Edge Article
DOI: 10.1039/C7SC00620A
Citation: Chem. Sci., 2017,8, 5030-5040
  • Open access: Creative Commons BY license
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    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

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