Home > Research > Publications & Outputs > Heparin and methionine oxidation promote the fo...

Associated organisational unit

Electronic data

  • acs.biochem

    Rights statement: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © 2017 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.biochem.6b01120

    Accepted author manuscript, 2.51 MB, PDF document

    Available under license: CC BY-NC: Creative Commons Attribution-NonCommercial 4.0 International License

Links

Text available via DOI:

View graph of relations

Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures.

Research output: Contribution to journalJournal articlepeer-review

Published
<mark>Journal publication date</mark>21/03/2017
<mark>Journal</mark>Biochemistry
Issue number11
Volume56
Number of pages13
Pages (from-to)1632-1644
Publication StatusPublished
Early online date19/12/16
<mark>Original language</mark>English

Abstract

Peptides derived from apolipoprotein A-I (apoA-I), the main component of high-density lipoprotein (HDL), constitute the main component of amyloid deposits that co-localise with atherosclerotic plaques. Here we investigate the molecular details of full-length, lipid-deprived apoA-I after assembly into insoluble aggregates under physiologically-relevant conditions known to induce aggregation in vitro. Unmodified apoA-I is shown to remain soluble at pH 7 for at least 3 days, retaining its native α-helical-rich structure. Upon acidification to pH 4, apoA-I rapidly assembles into insoluble non-fibrillar aggregates lacking the characteristic cross-beta features of amyloid. In the presence of heparin, the rate and thioflavin T responsiveness of the aggregates formed at pH 4 increase and short amyloid-like fibrils are observed, which give rise to amyloid-characteristic X-ray reflections at 4.7 and 10 Å. Solid-state NMR (SSNMR) and synchrotron radiation circular dichroism (SRCD) spectroscopy of fibrils formed in the presence of heparin retain some α-helical characteristics together with new β-sheet structures. Interestingly, SSNMR and indicates a similar molecular structure of aggregates formed in the absence of heparin at pH 6 after oxidation of the three methionine residues, although their morphology is rather different from the heparin-derived fibrils. We propose a model for apoA-I aggregation in which perturbations of an 4-helix bundle-like structure, induced by interactions of heparin or methionine oxidation, cause the partially helical N-terminal residues to disengage from the remaining, intact helices, thereby allowing self-assembly via β-strand associations.

Bibliographic note

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © 2017 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.biochem.6b01120