The Library Derived 4554W Peptide Inhibits Primary Nucleation of α-Synuclein

Meade, Richard M.; Morris, Kimberley J.; Watt, Kathryn J.C.; Williams, Robert J.; Mason, Jody M.

doi:10.1016/j.jmb.2020.11.005

Cited by 11 publications

(12 citation statements)

References 43 publications

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“…In addition, we show data for α-synuclein in the presence and absence of a therapeutic peptide (KDGIVNGVKA), designed to prevent aggregation to the toxic species (as we have reported previously) ( Jain et al, 2013 ). This peptide is based on residues 45–54 of the α-synuclein sequence ( Figure 4A ; green coloration), and therefore, binding will be in that location ( Meade et al, 2020 ), and we do not expect the variants to alter this binding given they are not within this sequence. This peptide has been shown to bind to a partially aggregated form of α-synuclein ( Meade et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

“…This peptide is based on residues 45–54 of the α-synuclein sequence ( Figure 4A ; green coloration), and therefore, binding will be in that location ( Meade et al, 2020 ), and we do not expect the variants to alter this binding given they are not within this sequence. This peptide has been shown to bind to a partially aggregated form of α-synuclein ( Meade et al, 2020 ). Figure 4B shows the

value extracted from the REES data from independent fits [no shared

value] to each of the α-synuclein variants and in the presence of the therapeutic peptide.…”

Section: Resultsmentioning

confidence: 99%

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A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability

Kwok

Camacho

Winter

et al. 2021

Front. Mol. Biosci.

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It is now over 30 years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. While there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the tryptophan REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides, to multitryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibodies in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating biomolecular simulation with experimental data to yield novel insights.

show abstract

Section: Resultsmentioning

confidence: 99%

value extracted from the REES data from independent fits [no shared

value] to each of the α-synuclein variants and in the presence of the therapeutic peptide.…”

Section: Resultsmentioning

confidence: 99%

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability

Kwok

Camacho

Winter

et al. 2021

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…25 In addition, we show data for α-synuclein in the presence and absence of a therapeutic peptide (KDGIVNGVKA), designed to prevent aggregation to the toxic species (as we have reported previously). 26 This peptide is based on residues 45-54 of the αsynuclein sequence (Figure 3A; green colouration) and therefore binding will be in that location. 26 This peptide has been shown to bind to a partially aggregated form of αsynuclein.…”

Section: Changes In Bothmentioning

confidence: 99%

“…26 This peptide is based on residues 45-54 of the αsynuclein sequence (Figure 3A; green colouration) and therefore binding will be in that location. 26 This peptide has been shown to bind to a partially aggregated form of αsynuclein. 26 Figure 3B shows the ( ) value extracted from the REES data from independent fits (no shared ( ) value) to each of the α-synuclein variants and in the presence of the therapeutic peptide.…”

Section: Changes In Bothmentioning

confidence: 99%

“…26 This peptide has been shown to bind to a partially aggregated form of αsynuclein. 26 Figure 3B shows the ( ) value extracted from the REES data from independent fits (no shared ( ) value) to each of the α-synuclein variants and in the presence of the therapeutic peptide. The ( ) values vary between ~385 and ~425 nm (noting the very large attendant error values in Figure 3B) with an average ( ) of 400.4 ± 15.4 nm.…”

Section: Changes In Bothmentioning

confidence: 99%

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A thermodynamic model for interpreting tryptophan excitation-energy-dependent fluorescence spectra provides insight into protein conformational sampling and stability

Kwok

Camacho

Winter

et al. 2021

Preprint

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It is now over thirty years since Demchenko and Ladokhin first posited the potential of the tryptophan red edge excitation shift (REES) effect to capture information on protein molecular dynamics. Whilst there have been many key efforts in the intervening years, a biophysical thermodynamic model to quantify the relationship between the REES effect and protein flexibility has been lacking. Without such a model the full potential of the REES effect cannot be realized. Here, we present a thermodynamic model of the protein REES effect that captures information on protein conformational flexibility, even with proteins containing multiple tryptophan residues. Our study incorporates exemplars at every scale, from tryptophan in solution, single tryptophan peptides to multi-tryptophan proteins, with examples including a structurally disordered peptide, de novo designed enzyme, human regulatory protein, therapeutic monoclonal antibody in active commercial development, and a mesophilic and hyperthermophilic enzyme. Combined, our model and data suggest a route forward for the experimental measurement of the protein REES effect and point to the potential for integrating bimolecular simulation with experimental data to yield novel insights.

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Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants

Watt

Meade

Williams

et al. 2022

Journal of Biological Chemistry

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The Library Derived 4554W Peptide Inhibits Primary Nucleation of α-Synuclein

Cited by 11 publications

References 43 publications

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability

A Thermodynamic Model for Interpreting Tryptophan Excitation-Energy-Dependent Fluorescence Spectra Provides Insight Into Protein Conformational Sampling and Stability

A thermodynamic model for interpreting tryptophan excitation-energy-dependent fluorescence spectra provides insight into protein conformational sampling and stability

Anionic lipid vesicles have differential effects on the aggregation of early onset-associated α-synuclein missense mutants

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