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

Lydia M. Young, Ling Hsien Tu, Daniel P. Raleigh, Alison E. Ashcroft, Sheena E. Radford

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5030-5040
Number of pages11
JournalChemical Science
Volume8
Issue number7
DOIs
Publication statusPublished - 2017 Jan 1

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Oligomers
Amyloid
Copolymerization
Islet Amyloid Polypeptide
Electrospray ionization
Mass spectrometry
Agglomeration
Ions
Seed
Proteins
Monomers
Fluorescence
Polymerization
Peptides

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers. / Young, Lydia M.; Tu, Ling Hsien; Raleigh, Daniel P.; Ashcroft, Alison E.; Radford, Sheena E.

In: Chemical Science, Vol. 8, No. 7, 01.01.2017, p. 5030-5040.

Research output: Contribution to journalArticle

Young, Lydia M. ; Tu, Ling Hsien ; Raleigh, Daniel P. ; Ashcroft, Alison E. ; Radford, Sheena E. / Understanding co-polymerization in amyloid formation by direct observation of mixed oligomers. In: Chemical Science. 2017 ; Vol. 8, No. 7. pp. 5030-5040.
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