Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils

Zlatic, C, Mao, Y, Todorova, N, Mok, Y, Howlett, G, Yarovsky, I, Gooley, P and Griffin, M 2018, 'Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils', FEBS Journal, vol. 285, no. 15, pp. 2799-2812.

Document type: Journal Article
Collection: Journal Articles

Title Polymorphism in disease-related apolipoprotein C-II amyloid fibrils: a structural model for rod-like fibrils
Author(s) Zlatic, C
Mao, Y
Todorova, N
Mok, Y
Howlett, G
Yarovsky, I
Gooley, P
Griffin, M
Year 2018
Journal name FEBS Journal
Volume number 285
Issue number 15
Start page 2799
End page 2812
Total pages 14
Publisher Wiley-Blackwell Publishing Ltd.
Abstract Human apolipoprotein (apo) C-II is one of several plasma apolipoproteins that form amyloid deposits in vivo and is an independent risk factor for cardiovascular disease. Lipid-free apoC-II readily self-assembles into twisted-ribbon amyloid fibrils but forms straight, rod-like amyloid fibrils in the presence of low concentrations of micellar phospholipids. Charge mutations exerted significantly different effects on rod-like fibril formation compared to their effects on twisted-ribbon fibril formation. For instance, the double mutant, K30D-D69K apoC-II, readily formed twisted-ribbon fibrils, while the rate of rod-like fibril formation in the presence of micellar phospholipid was negligible. Structural analysis of rod-like apoC-II fibrils, using hydrogendeuterium exchange and NMR analysis showed exchange protection consistent with a core cross-ß structure comprising the C-terminal 5876 region. Molecular dynamics simulations of fibril arrangements for this region favoured a parallel cross-ß structure. X-ray fibre diffraction data for aligned rod-like fibrils showed a major meridional spacing at 4.6 Å and equatorial spacings at 9.7, 23.8 and 46.6 Å. The latter two equatorial spacings are not observed for aligned twisted-ribbon fibrils and are predicted for a model involving two cross-ß fibrils in an off-set antiparallel structure with four apoC-II units per rise of the ß-sheet. This model is consistent with the mutational effects on rod-like apoC-II fibril formation. The lipid-dependent polymorphisms exhibited by apoC-II fibrils could determine the properties of apoC-II in renal amyloid deposits and their potential role in the development of cardiovascular disease.
Subject Condensed Matter Physics not elsewhere classified
Keyword(s) amyloid fibrils
apolipoprotein C-II
cross-beta structure
protein misfolding
DOI - identifier 10.1111/febs.14517
Copyright notice © 2018 Federation of European Biochemical Societies
ISSN 1742-464X
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