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    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

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

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Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures. / Townsend, David John; Hughes, Eleri; Hussain, Rohanah et al.
In: Biochemistry, Vol. 56, No. 11, 21.03.2017, p. 1632-1644.

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Townsend DJ, Hughes E, Hussain R, Siligardi G, Baldock SJ, Madine J et al. Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures. Biochemistry. 2017 Mar 21;56(11):1632-1644. Epub 2016 Dec 19. doi: 10.1021/acs.biochem.6b01120

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@article{641dc66257b44ebf90ebe9e9b867dda5,
title = "Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures.",
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 {\AA}. 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.",
author = "Townsend, {David John} and Eleri Hughes and Rohanah Hussain and Giuliano Siligardi and Baldock, {Sara Jane} and Jillian Madine and Middleton, {David Andrew}",
note = "This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright {\textcopyright} 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",
year = "2017",
month = mar,
day = "21",
doi = "10.1021/acs.biochem.6b01120",
language = "English",
volume = "56",
pages = "1632--1644",
journal = "Biochemistry",
issn = "0006-2960",
publisher = "American Chemical Society",
number = "11",

}

RIS

TY - JOUR

T1 - Heparin and methionine oxidation promote the formation of apolipoprotein A-I amyloid comprising α-helical and β-sheet structures.

AU - Townsend, David John

AU - Hughes, Eleri

AU - Hussain, Rohanah

AU - Siligardi, Giuliano

AU - Baldock, Sara Jane

AU - Madine, Jillian

AU - Middleton, David Andrew

N1 - 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

PY - 2017/3/21

Y1 - 2017/3/21

N2 - 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.

AB - 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.

U2 - 10.1021/acs.biochem.6b01120

DO - 10.1021/acs.biochem.6b01120

M3 - Journal article

VL - 56

SP - 1632

EP - 1644

JO - Biochemistry

JF - Biochemistry

SN - 0006-2960

IS - 11

ER -