Binding of serum-derived amyloid-associated proteins to amyloid fibrils

Misumi, Yohei; Tabata, Yuri; Tasaki, Masayoshi; Obayashi, Konen; Yamakawa, Shiori; Nomura, Toshiya; Ueda, Mitsuharu

doi:10.1080/13506129.2022.2120800

Cited by 7 publications

(2 citation statements)

References 23 publications

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“…We should consider the possibility that ApoC-III is codeposited with amyloid, that is, not an amyloid precursor protein, as apolipoprotein A-I, apolipoprotein A-IV, apolipoprotein E, and ApoC-III have been shown to bind to amyloid fibrils in vitro . 17 Apolipoprotein A-IV and apolipoprotein E, in particular, are known as amyloid signature proteins because they universally codeposit with amyloid fibrils in vivo , regardless of the type of amyloid precursor protein. 37 For this reason, in humans, the diagnostic criteria for apolipoprotein A-IV amyloidosis based on mass spectrometry are defined as a high number of apolipoprotein A-IV peptides detected by mass spectrometry and the absence of other amyloidogenic proteins, 3 and this criterion is also used for apolipoprotein A-IV amyloidosis in animals.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein C-III amyloidosis in white lions (Panthera leo)

Kobayashi,

Iwaide,

Fukui

et al. 2024

Vet Pathol

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Apolipoprotein C-III (ApoC-III) amyloidosis in humans is a hereditary amyloidosis caused by a D25V mutation in the APOC3 gene. This condition has only been reported in a French family and not in animals. We analyzed a 19-year-old white lion ( Panthera leo) that died in a Japanese safari park and found renal amyloidosis characterized by severe deposition confined to the renal corticomedullary border zone. Mass spectrometry-based proteomic analysis identified ApoC-III as a major component of renal amyloid deposits. Amyloid deposits were also positive for ApoC-III by immunohistochemistry. Based on these results, this case was diagnosed as ApoC-III amyloidosis for the first time in nonhuman animals. Five additional white lions were also tested for amyloid deposition retrospectively. ApoC-III amyloid deposition was detected in 3 white lions aged 19 to 21 years but not in 2 cases aged 0.5 and 10 years. Genetic analysis of white and regular-colored lions revealed that the APOC3 sequences of the lions were identical, regardless of amyloid deposition. These results suggest that ApoC-III amyloidosis in lions, unlike in humans, may not be a hereditary condition but an age-related condition. Interestingly, lion ApoC-III has a Val30 substitution compared with other species of Panthera that have Met30. Structural predictions suggest that the conformation of ApoC-III with Met30 and ApoC-III with Val30 are almost identical, but this substitution may alter the ability to bind to lipids. As with the D25V mutation in human ApoC-III, the Val30 substitution in lions may increase the proportion of free ApoC-III, leading to amyloid formation.

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein C-III amyloidosis in white lions (Panthera leo)

Kobayashi,

Iwaide,

Fukui

et al. 2024

Vet Pathol

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“…1) indicate that structural destabilization and exposure of hydrophobic surfaces in the N-terminal helix bundle alone are not sufficient to trigger fibril formation by full-length apoA-I at neutral pH, consistent with previous studies 12,47 . Other factors such as oxidative modification of methionine residues [48][49][50] , proteolysis 51 , or interactions with amyloid-associated proteins 52 or heparan sulfate 53,54 may be required to initiate the conversion of full-length apoA-I into the amyloid fibrillar form at neutral pH.…”

Section: Discussionmentioning

confidence: 99%

Amyloidogenic 60–71 deletion/ValThr insertion mutation of apolipoprotein A-I generates a new aggregation-prone segment that promotes nucleation through entropic effects

Namba,

Ohgita,

Tamagaki-Asahina

et al. 2023

Sci Rep

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The N-terminal fragment of apolipoprotein A-I (apoA-I), comprising residues 1–83, contains three segments prone to aggregation: residues 14–22, 53–58, and 67–72. We previously demonstrated that residues 14–22 are critical in apoA-I fibril formation while residues 53–58 entropically drove the nucleation process. Here, we investigated the impact of amyloidogenic mutations (Δ60–71/VT, Δ70–72, and F71Y) located around residues 67–72 on fibril formation by the apoA-I 1–83 fragment. Thioflavin T fluorescence assay demonstrated that the Δ60–71/VT mutation significantly enhances both nucleation and fibril elongation rates, whereas the Δ70–72 and F71Y mutations had minimal effects. Circular dichroism measurements and microscopic observations revealed that all variant fragments formed straight fibrils, transitioning from random coils to β-sheet structures. Kinetic analysis demonstrated that primary nucleation is the dominant step in fibril formation, with fibril elongation reaching saturation at high protein concentrations. Thermodynamically, both nucleation and fibril elongation were enthalpically and entropically unfavorable in all apoA-I 1–83 variants, in which the entropic barrier of nucleation was almost eliminated for the Δ60–71/VT variant. Taken together, our results suggest the presence of new aggregation-prone segment in the Δ60–71/VT variant that promotes nucleation through entropic effects.

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Understanding and Overcoming Biochemical Diversity in AL Amyloidosis

Morgan

2023

Israel Journal of Chemistry

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Amyloid fibril deposition causes progressive tissue damage and organ failure in the systemic amyloid diseases, and therapies that suppress aggregation lead to clinical benefit. Small molecules that prevent aggregation by binding to precursor proteins are effective for amyloid transthyretin (ATTR) amyloidosis. However, in amyloid light chain (AL) amyloidosis, fibrils are formed by antibody light chains and every patient has a unique protein sequence that aggregates. The highly diverse sequences of these light chains appear to determine whether an individual is at risk of amyloidosis, the distribution of amyloid deposits and the progression of disease. Light chains are therefore challenging drug targets. This review explores the parallels between AL amyloidosis and ATTR amyloidosis to describe the discovery of small molecules that can stabilize light chains. These molecules have potential as therapies for AL amyloidosis, highlighting potential opportunities for drug discovery in other diseases of protein misfolding.

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Binding of serum-derived amyloid-associated proteins to amyloid fibrils

Cited by 7 publications

References 23 publications

Apolipoprotein C-III amyloidosis in white lions (Panthera leo)

Apolipoprotein C-III amyloidosis in white lions (Panthera leo)

Amyloidogenic 60–71 deletion/ValThr insertion mutation of apolipoprotein A-I generates a new aggregation-prone segment that promotes nucleation through entropic effects

Understanding and Overcoming Biochemical Diversity in AL Amyloidosis

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