Supramolecular Modulation of Structural Polymorphism in Pathogenic α‐Synuclein Fibrils Using Copper(II) Coordination

Choi, Tae Su; Lee, Won Jin; Han, Jong Yoon; Jung, Byung Chul; Wongkongkathep, Piriya; Loo, Joseph A.; Lee, Minjae; Kim, Hugh I.

doi:10.1002/ange.201712286

Cited by 4 publications

(4 citation statements)

References 36 publications

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“…A similar relationship between tau compaction and charge state was also observed for the singly CLR0l-bound C291A 4R-tau fragment, especially for the lower charge states (Figure S6). The TWIMS resolving power for these tau proteins is similar to our TWIMS measurements of another intrinsically disordered protein, α-synuclein [47, 51] and a recent TWIMS study of tau proteins [52]. …”

Section: Resultssupporting

confidence: 78%

Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

Nshanian

Lantz

Wongkongkathep

et al. 2018

J. Am. Soc. Mass Spectrom.

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Native top-down mass spectrometry (MS) and ion mobility spectrometry (IMS) were applied to characterize the interaction of a molecular tweezer assembly modulator, CLR01, with tau, a protein believed to be involved in a number of neurodegenerative disorders, including Alzheimer's disease. The tweezer CLR01 has been shown to inhibit aggregation of amyloidogenic polypeptides without toxic side effects. ESI-MS spectra for different forms of tau protein (full-length, fragments, phosphorylated, etc.) in the presence of CLR01 indicate a primary binding stoichiometry of 1:1. The relatively high charging of the protein measured from non-denaturing solutions is typical of intrinsically disordered proteins, such as tau. Top-down mass spectrometry using electron capture dissociation (ECD) is a tool used to determine not only the sites of post-translational modifications but also the binding site(s) of non-covalent interacting ligands to biomolecules. The intact protein and the protein-modulator complex were subjected to ECD-MS to obtain sequence information, map phosphorylation sites, and pinpoint the sites of inhibitor binding. The ESI-MS study of intact tau proteins indicates that top-down MS is amenable to the study of various tau isoforms and their post-translational modifications (PTMs). The ECD-MS data point to a CLR01 binding site in the microtubule-binding region of tau, spanning residues K294-K331, which includes a six-residue nucleating segment PHF6 (VQIVYK) implicated in aggregation. Furthermore, ion mobility experiments on the tau fragment in the presence of CLR01 and phosphorylated tau reveal a shift towards a more compact structure. The mass spectrometry study suggests a picture for the molecular mechanism of the modulation of protein-protein interactions in tau by CLR01. Graphical Abstract ᅟ.

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Section: Resultssupporting

confidence: 78%

Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

Nshanian

Lantz

Wongkongkathep

et al. 2018

J. Am. Soc. Mass Spectrom.

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“…In terms of the amyloid potential of the protein, as mentioned above, no significant differences were observed in the fibrillation kinetics between acetylated and non‐acetylated AS, whereas the fibrillation enhancement observed for AS at an equimolar Cu(II) stoichiometry did not occur with the acetylated variant of the protein (Moriarty et al, ). Indeed, a recent study showed that the conformation of the non‐acetylated AS monomer would be strained by macrochelation with Cu(II) at sites 1 and 2, thereby disrupting fibril elongation and promoting amyloid nucleation (Choi et al ). According to this study, this interaction leads to the formation of shortened, β‐sheet enriched fibrils (< 0.2 μM) that are rapidly transmitted and accumulated to neuronal cells, causing neuronal cell death, in sharp contrast to typical AS fibrils (ca 1 μM).…”

Section: Linking Post‐translational Modifications and Metal‐binding Imentioning

confidence: 99%

Effects of alpha‐synuclein post‐translational modifications on metal binding

González

Arcos-López

König

et al. 2019

Journal of Neurochemistry

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Parkinson’s disease is the second most common neurodegenerative disorder worldwide. Neurodegeneration in this pathology is characterized by the loss of dopaminergic neurons in the substantia nigra, coupled with cytoplasmic inclusions known as Lewy bodies containing α‐synuclein. The brain is an organ that concentrates metal ions, and there is emerging evidence that a break‐down in metal homeostasis may be a critical factor in a variety of neurodegenerative diseases. α‐synuclein has emerged as an important metal‐binding protein in the brain, whereas these interactions play an important role in its aggregation and might represent a link between protein aggregation, oxidative damage, and neuronal cell loss. Additionally, α‐synuclein undergoes several post‐translational modifications that regulate its structure and physiological function, and may be linked to the aggregation and/or oligomer formation. This review is focused on the interaction of this protein with physiologically relevant metal ions, highlighting the cases where metal‐AS interactions profile as key modulators for its structural, aggregation, and membrane‐binding properties. The impact of α‐synuclein phosphorylation and N‐terminal acetylation in the metal‐binding properties of the protein are also discussed, underscoring a potential interplay between PTMs and metal ion binding in regulating α‐synuclein physiological functions and its role in pathology. This article is part of the Special Issue “Synuclein”.

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“…These shortened fibrils exhibit rapid transmission and accumulation in neuronal cells, ultimately resulting in neuronal cell death. This is in stark contrast to typical αSyn fibrils, which are larger in size (approximately 1 μm) [ 38 ]. TETA (triethylenetetramine) has been demonstrated to mitigate the harmful impact of copper ions on the toxic spread of αSyn fibrils.…”

Section: Factors Influencing Protein Aggregationmentioning

confidence: 93%

“…H50 is situated within the β-sheet-aligned core region of αSyn, and the conformation of the αSyn-Cu 2+ complex is constrained specifically within residues 1–50. As a result, the structural reorientation of residues 1–50, which is necessary for the assembly onto the αSyn nucleus, is altered [ 38 ]. This is further supported by evidence that H50 in mature fibrils cannot coordinate copper [ 39 ].…”

Section: Factors Influencing Protein Aggregationmentioning

confidence: 99%

Unveiling the Effects of Copper Ions in the Aggregation of Amyloidogenic Proteins

Oliveri

2023

Molecules

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Amyloid diseases have become a global concern due to their increasing prevalence. Transition metals, including copper, can affect the aggregation of the pathological proteins involved in these diseases. Copper ions play vital roles in organisms, but the disruption of their homeostasis can negatively impact neuronal function and contribute to amyloid diseases with toxic protein aggregates, oxidative stress, mitochondrial dysfunction, impaired cellular signaling, inflammation, and cell death. Gaining insight into the imbalance of copper ions and its impact on protein folding and aggregation is crucial for developing focused therapies. This review examines the influence of copper ions on significant amyloid proteins/peptides, offering a comprehensive overview of the current understanding in this field.

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Supramolecular Modulation of Structural Polymorphism in Pathogenic α‐Synuclein Fibrils Using Copper(II) Coordination

Abstract: This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record.

Cited by 4 publications

References 36 publications

Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

Native Top-Down Mass Spectrometry and Ion Mobility Spectrometry of the Interaction of Tau Protein with a Molecular Tweezer Assembly Modulator

Effects of alpha‐synuclein post‐translational modifications on metal binding

Unveiling the Effects of Copper Ions in the Aggregation of Amyloidogenic Proteins

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