A Structural Core Within Apolipoprotein C-II Amyloid Fibrils Identified Using Hydrogen Exchange and Proteolysis

Wilson, Lewis; Mok, Yee-Foong; Binger, Katrina J.; Griffin, Michael D. W.; Mertens, Haydyn D. T.; Lin, Feng; Wade, John D.; Gooley, Paul R.; Howlett, Geoffrey J.

doi:10.1016/j.jmb.2006.12.040

Cited by 53 publications

(60 citation statements)

References 46 publications

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“…[19][20][21] The molecular architecture of fibrils formed by different proteins differs with respect to amount of cross-b structure, strand orientation and disposition of the core amyloid structure within the protein. 22 Despite their similar nature, a distinction should be made between amyloid fibril formation and protein aggregation. At high protein concentration under physiological conditions, misfolded protein molecules can form amorphous aggregates.…”

Section: Introductionmentioning

confidence: 99%

“…27 While such regions may be due to errors in secondary structure prediction algorithms, such discordant a-helices have been verified experimentally in some cases. They are seen to occur in the prion protein (positions 179-191), the b-amyloid peptide (positions [16][17][18][19][20][21][22][23] and the lung surfactant protein (positions 12-27), as well as several proteins which although not known to be amyloidogenic in vivo, have been found to produce fibrils in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Amyloidogenic sequences in native protein structures

Tzotzos

Doig

2010

Protein Science

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Numerous short peptides have been shown to form b-sheet amyloid aggregates in vitro.Proteins that contain such sequences are likely to be problematic for a cell, due to their potential to aggregate into toxic structures. We investigated the structures of 30 proteins containing 45 sequences known to form amyloid, to see how the proteins cope with the presence of these potentially toxic sequences, studying secondary structure, hydrogen-bonding, solvent accessible surface area and hydrophobicity. We identified two mechanisms by which proteins avoid aggregation: Firstly, amyloidogenic sequences are often found within helices, despite their inherent preference to form b structure. Helices may offer a selective advantage, since in order to form amyloid the sequence will presumably have to first unfold and then refold into a b structure. Secondly, amyloidogenic sequences that are found in b structure are usually buried within the protein. Surface exposed amyloidogenic sequences are not tolerated in strands, presumably because they lead to protein aggregation via assembly of the amyloidogenic regions. The use of a-helices, where amyloidogenic sequences are forced into helix, despite their intrinsic preference for b structure, is thus a widespread mechanism to avoid protein aggregation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amyloidogenic sequences in native protein structures

Tzotzos

Doig

2010

Protein Science

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“…Some of these applications include purification of fibrils by a selective degradation of protease-sensitive amorphous aggregates (21), discrimination between benign cellular prion protein and its pathogenic prion isoforms (22), and testing overall amyloid stability (23). The approach based on susceptibility to proteases proved particularly insightful in several in vitro studies probing different stages of protein fibrillation (24) or mapping core regions of mature amyloid structures (25)(26)(27)(28).…”

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confidence: 99%

Highly Amyloidogenic Two-chain Peptide Fragments Are Released upon Partial Digestion of Insulin with Pepsin

Piejko

Dec

Babenko

et al. 2015

Journal of Biological Chemistry

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Background: Insulin is a model amyloidogenic protein.Results: Limited proteolysis of bovine insulin dimers with pepsin releases highly fibrillation-prone two-chain fragments. Conclusion: Dynamics of the disulfide-bonded N-terminal fragments of A-and B-chains may strongly contribute to insulin amyloidogenesis. Significance: Highly aggregation-prone regions of protein molecules may be revealed by partial proteolysis of the native state.

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“…Such self-association has been proposed to be important for stabilising apolipoprotein structures and may infl uence the function of lipoprotein particles (e. g. apoA-I and apoA-IV dimers). ApoC-II peptides have also been used to elucidate misfolding events and molecular interactions involved in apoC-II aggregation (Wilson et al 2007 ;Legge et al 2007 ;Griffi n et al 2012 ). These peptides are derived from the amyloidogenic regions of apoC-II and undergo many of the processes involved in the misfolding and amyloid fi bril formation by the full-length protein.…”

Section: 7mentioning

confidence: 99%

“…Fibre diffraction experiments show a classical cross-β diffraction pattern with refl ections at 4.67 Å and 9.46 Å, indicating the spacing between β-strands in the fi bril axis and the average spacing between β-sheets in the fi bril cross section, respectively ) STEM revealed that the fi brils contain approximately one molecule of apoC-II per 4.7 Å rise in the long axis of the fi bril, and hydrogen/deuterium exchange data indicated two protected regions in residues 20-36 and 58-74 (Wilson et al 2007 ) that are implicated in formation of the amyloid core. Recently, these and other observations led to the development of a "letter-G-like" β-strand-loop-β-strand structural model for an apoC-II unit within a mature amyloid fi bril (Fig.…”

Section: Introductionmentioning

confidence: 99%

The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II

Ryan

Mok

Howlett

et al. 2015

Advances in Experimental Medicine and Biology

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Apolipoproteins are a key component of lipid transport in the circulatory system and share a number of structural features that facilitate this role. When bound to lipoprotein particles, these proteins are relatively stable. However, in the absence of lipids they display conformational instability and a propensity to aggregate into amyloid fibrils. Apolipoprotein C-II (apoC-II) is a member of the apolipoprotein family that has been well characterised in terms of its misfolding and aggregation. In the absence of lipid, and at physiological ionic strength and pH, apoC-II readily forms amyloid fibrils with a twisted ribbon-like morphology that are amenable to a range of biophysical and structural analyses. Consistent with its lipid binding function, the misfolding and aggregation of apoC-II are substantially affected by the presence of lipid. Short-chain phospholipids at submicellar concentrations significantly accelerate amyloid formation by inducing a tetrameric form of apoC-II that can nucleate fibril aggregation. Conversely, phospholipid micelles and bilayers inhibit the formation of apoC-II ribbon-type fibrils, but induce slow formation of amyloid with a distinct straight fibril morphology. Our studies of the effects of lipid at each stage of amyloid formation, detailed in this chapter, have revealed complex behaviour dependent on the chemical nature of the lipid molecule, its association state, and the protein:lipid ratio.

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A Structural Core Within Apolipoprotein C-II Amyloid Fibrils Identified Using Hydrogen Exchange and Proteolysis

Cited by 53 publications

References 46 publications

Amyloidogenic sequences in native protein structures

Amyloidogenic sequences in native protein structures

Highly Amyloidogenic Two-chain Peptide Fragments Are Released upon Partial Digestion of Insulin with Pepsin

The Role of Lipid in Misfolding and Amyloid Fibril Formation by Apolipoprotein C-II

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