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

Townsend, David John and Hughes, Eleri and Hussain, Rohanah and Siligardi, Giuliano and Baldock, Sara Jane and Madine, Jillian and Middleton, David Andrew (2017) Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures. Biochemistry, 56 (11). pp. 1632-1644. ISSN 0006-2960

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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.

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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
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05 Jan 2017 14:54
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26 Jan 2024 01:20