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

Townsend, D, Hughes, E, Hussain, R, Siligardi, G, Baldock, SJ, Madine, J ORCID: 0000-0001-9963-5871 and Middleton, DA (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.

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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 colocalize 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 nonfibrillar aggregates lacking the characteristic cross-β 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 nuclear magnetic resonance (SSNMR) and synchrotron radiation circular dichroism spectroscopy of fibrils formed in the presence of heparin show they retain some α-helical characteristics together with new β-sheet structures. Interestingly, SSNMR 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 that of the heparin-derived fibrils. We propose a model for apoA-I aggregation in which perturbations of a four-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.

Item Type:	Article
Uncontrolled Keywords:	nanofibers, peptides and proteins, monomers, aggregation heparin
Depositing User:	Symplectic Admin
Date Deposited:	10 Jan 2017 10:03
Last Modified:	19 Jan 2023 07:20
DOI:	10.1021/acs.biochem.6b01120
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3005143