A Structural Model for Apolipoprotein C-II Amyloid Fibrils: Experimental Characterization and Molecular Dynamics Simulations

Teoh, Chai Lean; Pham, Chi L.L.; Todorova, Nevena; Hung, Andrew; Lincoln, Craig N.; Lees, Emma E.; Lam, Yuen-Han; Binger, Katrina J.; Thomson, Neil H.; Radford, Sheena E.; Smith, Trevor A.; Müller, Shirley A.; Engel, Andréas; Griffin, Michael D. W.; Yarovsky, Irene; Gooley, Paul R.; Howlett, Geoffrey J.

doi:10.1016/j.jmb.2010.12.006

Cited by 45 publications

(97 citation statements)

References 96 publications

(101 reference statements)

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“…The strong equatorial peak centered on 9.46 Å represents the average spacing between β-sheets in the fibril cross-section. The equatorial axis radial profile shows that this is the only unique and resolved reflection on this axis, suggesting that the defined structure across the fibril cross-section is simple and does not contain superstructure resulting from lateral packing of filaments (Teoh et al, 2011a).…”

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 92%

“…TEM images of negatively stained apoC-II fibrils (Fig. 1) revealed long unbranched fibrils of twisted ribbon morphology with widths of approximately 120-130 Å and a typical length of several microns or more (Hatters et al, 2000;Hatters et al, 2003;Teoh et al, 2011a). These ribbons display a regular twist and, unusually, a small number take the form of closed loops (Hatters et al, 2000;Hatters et al, 2003;Teoh et al, 2011a).…”

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 96%

“…The structure of apoC-II amyloid fibrils has been probed by Xray diffraction Teoh et al, 2011a). The diffraction image of aligned apoC-II fibrils shows a classical cross-β diffraction pattern dominated by perpendicular reflections on the meridional and equatorial axes, where the sharp meridional peak at 4.67 Å indicates the spacing between β-strands within the fibrils (Teoh et al, 2011a).…”

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

“…The diffraction image of aligned apoC-II fibrils shows a classical cross-β diffraction pattern dominated by perpendicular reflections on the meridional and equatorial axes, where the sharp meridional peak at 4.67 Å indicates the spacing between β-strands within the fibrils (Teoh et al, 2011a). The strong equatorial peak centered on 9.46 Å represents the average spacing between β-sheets in the fibril cross-section.…”

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

“…Both models approximate the distribution of loop lengths measured from electron micrographs . Atomic force microscopy performed under aqueous conditions, where the sample remains fully hydrated and tip-sample adhesion effects are mitigated, indicated a modal thickness of 37 Å for the height distribution of apoC-II amyloid fibrils (Teoh et al, 2011a). Examination of apoC-II fibrils using scanning transmission electron microscopy (STEM) indicated that the fibrils are composed of one apoC-II molecule per 4.7 Å rise of the cross-β structure (Teoh et al, 2011a).…”

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

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Apolipoproteins and amyloid fibril formation in atherosclerosis

2011

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Amyloid fibrils arise from the aggregation of misfolded proteins into highly-ordered structures. The accumulation of these fibrils along with some non-fibrillar constituents within amyloid plaques is associated with the pathogenesis of several human degenerative diseases. A number of plasma apolipoproteins, including apolipoprotein (apo) A-I, apoA-II, apoC-II and apoE are implicated in amyloid formation or influence amyloid formation by other proteins. We review present knowledge of amyloid formation by apolipoproteins in disease, with particular focus on atherosclerosis. Further insights into the molecular mechanisms underlying their amyloidogenic propensity are obtained from in vitro studies which describe factors affecting apolipoprotein amyloid fibril formation and interactions. Additionally, we outline the evidence that amyloid fibril formation by apolipoproteins might play a role in the development and progression of atherosclerosis, and highlight possible molecular mechanisms that could contribute to the pathogenesis of this disease.

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Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 92%

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 96%

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

Section: Structural Analysis Of Apoc-ii Amyloid Fibrilsmentioning

confidence: 99%

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Apolipoproteins and amyloid fibril formation in atherosclerosis

2011

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Creation of Aggregation‐Defective α‐Synuclein Variants by Engineering the Sequence Connecting β‐Strand‐Forming Domains

et al. 2011

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The aggregation of α-synuclein (αS), which is implicated in the pathology of Parkinson's disease, produces fibrils in which layers of parallel, in-register β-sheet-loop-β-sheets are formed. The effects of sequence variation in the loop-forming region (referred to as the linker region) on αS aggregation have yet to be systematically studied. In the study described here, we created and characterized αS variants containing mutations in the linker regions. Our results indicate that although the physicochemical properties of the linker region, evaluated based on an intrinsic property of a single amino acid, still play a significant role in aggregation, additional factors can also determine aggregation of αS linker mutants. Our analyses suggest that these factors include a pairwise potential for parallel in-register β-sheet formation. A linker variant displaying significantly reduced self-aggregation interfered with αS aggregation by inhibiting the conversion of αS soluble species to αS insoluble fibrils. We anticipate that linker mutations could serve as a novel method of creating αS variants that are aggregation-defective and/or inhibit αS aggregation.

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An alternative structural isoform in amyloid‐like aggregates formed from thermally denatured human γD‐crystallin

2014

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The eye lens protein cD-crystallin contributes to cataract formation in the lens. In vitro experiments show that cD-crystallin has a high propensity to form amyloid fibers when denatured, and that denaturation by acid or UV-B photodamage results in its C-terminal domain forming the b-sheet core of amyloid fibers. Here, we show that thermal denaturation results in sheet-like aggregates that contain cross-linked oligomers of the protein, according to transmission electron microscopy and SDS-PAGE. We use two-dimensional infrared spectroscopy to show that these aggregates have an amyloid-like secondary structure with extended b-sheets, and use isotope dilution experiments to show that each protein contributes approximately one b-strand to each b-sheet in the aggregates. Using segmental 13 C labeling, we show that the organization of the protein's two domains in thermally induced aggregates results in a previously unobserved structure in which both the N-terminal and C-terminal domains contribute to b-sheets. We propose a model for the structural organization of the aggregates and attribute the recruitment of the N-terminal domain into the fiber structure to intermolecular cross linking.

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A Structural Model for Apolipoprotein C-II Amyloid Fibrils: Experimental Characterization and Molecular Dynamics Simulations

Cited by 45 publications

References 96 publications

Apolipoproteins and amyloid fibril formation in atherosclerosis

Apolipoproteins and amyloid fibril formation in atherosclerosis

Creation of Aggregation‐Defective α‐Synuclein Variants by Engineering the Sequence Connecting β‐Strand‐Forming Domains

An alternative structural isoform in amyloid‐like aggregates formed from thermally denatured human γD‐crystallin

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