Analysis of Core Region from Egg White Lysozyme Forming Amyloid Fibrils

Tokunaga, Yuhei; Sakakibara, Yukako; Kamada, Yoshiki; Watanabe, Keiichi; Sugimoto, Yasushi

doi:10.7150/ijbs.5380

Cited by 80 publications

(64 citation statements)

References 46 publications

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“…Regarding the variants of human lysozyme used in the present examination (I56T, F57I, W64R and D67H; Fig. 1), the mutation sites are concentrated in the position surrounding the core region at the β-domain [16], of which nine amino acids (55G-63Y) are indispensable for amyloid fibril formation [22,23]. Comparisons of the conformational structures of these lysozymes (our unpublished results and refs.…”

Section: Discussionmentioning

confidence: 97%

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Kamada

Kusakabe

Sugimoto

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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Section: Discussionmentioning

confidence: 97%

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Kamada

Kusakabe

Sugimoto

2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…According to Sugimoto and colleagues, 52 a peptide located in the β-domain of HEWL referred to as K peptide (consisting of residues 54−62 GILQINSRW) was found to act as a core for aggregation and subsequent amyloid fibril formation. Likewise, Lara et al recently found the shorter peptide sequence ILQINS to be highly amyloidogenic at room temperature.…”

Section: ■ Discussionmentioning

confidence: 99%

Myricetin Prevents Fibrillogenesis of Hen Egg White Lysozyme

Wang

Chang

et al. 2014

J. Agric. Food Chem.

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Myricetin is a natural flavonol found in many grapes, berries, fruits, vegetables, and herbs as well as other plants. Recent studies have identified potential antiamyloidogenic activity for this compound. In this study, the kinetics of amyloid fibril formation by hen egg white lysozyme (HEWL) and the antifibril-forming activity of myricetin were investigated. We demonstrate that myricetin significantly inhibits the fibrillation of HEWL and the inhibitory effect is dose-dependent. Interestingly, the inhibitory effect toward HEWL fibrillation was stronger than that exerted by the previously characterized fibril-forming inhibitor quercetin, which has high structural similarity with myricetin. Spectrofluorometric and computational studies suggest that the mechanism underlying the inhibitory action of myricetin at a molecular level is to reduce the population of partially unfolded HEWL intermediates. This action is achieved by the tight binding of myricetin to the aggregation-prone region of the β-domain of HEWL and linking to the relatively stable α-domain, thus resulting in the inhibition of amyloid fibril formation. KEYWORDS: myricetin, lysozyme, amyloid, molecular dynamics simulation, molecular docking ■ INTRODUCTIONAmyloid diseases are characterized by conformational changes of certain proteins, which lead to intracellular or extracellular aggregation, eventually resulting in fibrillar amyloid deposits in the affected tissue. Currently there are approximately 30 extracellular fibril proteins known to be associated with human amyloidosis. 1 The so-called "hereditary non-neuropathic systemic amyloidosis" is associated with two lysozyme variants (I56T and D67H), which were identified in the early 1990s 2 and other naturally occurring amyloidogenic variants (F57I, F57I/ T70N, W64R, and T70N/W112R) discovered more recently. 3−5 The pathological characteristics of these amyloidoses includes the deposition of the full-length protein variants in organs, such as liver, spleen, and kidneys. 2 At present there are still no effective treatments for amyloid diseases such as Alzheimer's disease, systemic amyloidosis, familial amyloid polyneuropathy, and Creutzfeldt-Jakob disease, and all drugs in development that target Alzheimer's disease have failed at various stages of clinical trials. 6 However, the identification and development of small molecules that inhibit fibril formation by amyloidogenic proteins is a promising area of research. 7,8 Among the most promising small-molecule inhibitors, the naturally occurring polyphenols show the most effective antiamyloidogenic activity. 9 A group of polyphenols found in green tea (GTPs) including (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epigallocatechin gallate (EGCG) have been reported as effective inhibitors of alkali-saltinduced fibrillogenesis of hen egg white lysozyme (HEWL) with ECG as the most potent polyphenol. 10 A previous report demonstrated that curcumin can also inhibit the aggregation and formation of amyloid fibrillation of HEWL ...

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“…Amyloidogenicity of this protein is thought to arise from the enhanced propensity of its mutants to adopt a partially unfolded aggregationprone conformation (Frare et al 2004). Specific segment in hen egg white lysozyme encompassing residues 54-62 was recently proposed to serve as the amyloid core that triggers fibril formation (Tokunaga et al 2013).…”

Section: Effects Of Protein Fibrils and Oligomers On The Membrane Strmentioning

confidence: 99%

Interactions of Lipid Membranes with Fibrillar Protein Aggregates

Gorbenko

Trusova

Girych

et al. 2015

Advances in Experimental Medicine and Biology

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Amyloid fibrils are an intriguing class of protein aggregates with distinct physicochemical, structural and morphological properties. They display peculiar membrane-binding behavior, thus adding complexity to the problem of protein-lipid interactions. The consensus that emerged during the past decade is that amyloid cytotoxicity arises from a continuum of cross-β-sheet assemblies including mature fibrils. Based on literature survey and our own data, in this chapter we address several aspects of fibril-lipid interactions, including (i) the effects of amyloid assemblies on molecular organization of lipid bilayer; (ii) competition between fibrillar and monomeric membrane-associating proteins for binding to the lipid surface; and (iii) the effects of lipids on the structural morphology of fibrillar aggregates. To illustrate some of the processes occurring in fibril-lipid systems, we present and analyze fluorescence data reporting on lipid bilayer interactions with fibrillar lysozyme and with the N-terminal 83-residue fragment of amyloidogenic mutant apolipoprotein A-I, 1-83/G26R/W@8. The results help understand possible mechanisms of interaction and mutual remodeling of amyloid fibers and lipid membranes, which may contribute to amyloid cytotoxicity.

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Analysis of Core Region from Egg White Lysozyme Forming Amyloid Fibrils

Cited by 80 publications

References 46 publications

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Amyloidogenic lysozymes accumulate in the endoplasmic reticulum accompanied by the augmentation of ER stress signals

Myricetin Prevents Fibrillogenesis of Hen Egg White Lysozyme

Interactions of Lipid Membranes with Fibrillar Protein Aggregates

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