Dataset Information

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-? Intermediates Revealing that Self-Assembly Is Required for A?-Induced Cytotoxicity.

ABSTRACT: Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-? (A?) forms DiY in vitro and DiY-cross-linked A? is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of A?42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of A?42 (vA?) with wild-type A?42. Oxidation results in the formation of trapped wild-type A? assemblies with increased DiY cross-links that are unable to elongate further. Assembly-incompetent vA? and trapped A? assemblies are non-toxic to neuroblastoma cells at all stages of self-assembly, in contrast to oligomeric, non-cross-linked A?. These findings point to a mechanism of toxicity that necessitates dynamic self-assembly whereby trapped A? assemblies and assembly-incompetent variant A? are unable to result in cell death.

SUBMITTER: Maina MB

PROVIDER: S-EPMC7516296 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity.

Maina Mahmoud B MB Burra Gunasekhar G Al-Hilaly Youssra K YK Mengham Kurtis K Fennell Kate K Serpell Louise C LC

iScience 20200906 10

Dityrosine (DiY), via the cross-linking of tyrosine residues, is a marker of protein oxidation, which increases with aging. Amyloid-β (Aβ) forms DiY <i>in vitro</i> and DiY-cross-linked Aβ is found in the brains of patients with Alzheimer disease. Metal- or UV- catalyzed oxidation of Aβ42 results in an increase in DiY cross-links. Using DiY as a marker of oxidation, we compare the self-assembly propensity and DiY cross-link formation for a non-assembly competent variant of Aβ42 (vAβ) with wild-t ...[more]

PMID: 33083713

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Project description:In the present work, the conformational dynamics and folding pathways of i-motif DNA were studied in solution and in the gas-phase as a function of the solution pH conditions using circular dichroism (CD), photoacoustic calorimetry analysis (PAC), trapped ion mobility spectrometry-mass spectrometry (TIMS-MS), and molecular dynamics (MD). Solution studies showed at thermodynamic equilibrium the existence of a two-state folding mechanism, whereas during the pH = 7.0 → 4.5 transition a fast and slow phase (ΔHfast + ΔHslow = 43 ± 7 kcal mol-1) with a volume change associated with the formation of hemiprotonated cytosine base pairs and concomitant collapse of the i-motif oligonucleotide into a compact conformation were observed. TIMS-MS experiments showed that gas-phase, kinetically trapped i-motif DNA intermediates produced by nanoESI are preserved, with relative abundances depending on the solution pH conditions. In particular, a folded i-motif DNA structure was observed in nanoESI-TIMS-MS for low charge states in both positive and negative ion mode (e.g., z = ±3 to ±5) at low pH conditions. As solution pH increases, the cytosine neutralization leads to the loss of cytosine-cytosine+ (C·CH+) base pairing in the CCC strands and in those conditions we observe partially unfolded i-motif DNA conformations in nanoESI-TIMS-MS for higher charge states (e.g., z = -6 to -9). Collisional induced activation prior to TIMS-MS showed the existence of multiple local free energy minima, associated with the i-motif DNA unfolding at z = -6 charge state. For the first time, candidate gas-phase structures are proposed based on mobility measurements of the i-motif DNA unfolding pathway. Moreover, the inspection of partially unfolded i-motif DNA structures (z = -7 and z = -8 charge states) showed that the presence of inner cations may or may not induce conformational changes in the gas-phase. For example, incorporation of ammonium adducts does not lead to major conformational changes while sodium adducts may lead to the formation of sodium mediated bonds between two negatively charged sides inducing the stabilization towards more compact structures in new local, free energy minima in the gas-phase.

Dataset Information

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-? Intermediates Revealing that Self-Assembly Is Required for A?-Induced Cytotoxicity.

Publications

Metal- and UV- Catalyzed Oxidation Results in Trapped Amyloid-β Intermediates Revealing that Self-Assembly Is Required for Aβ-Induced Cytotoxicity.

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