Dimers of D76N-β2-microglobulin display potent antiamyloid aggregation activity

Maya-Martinez, Roberto; Xu, Yong; Guthertz, Nicolas; Walko, Martin; Karamanos, Theodoros K.; Sobott, Frank; Breeze, Alexander L.; Radford, Sheena E.

doi:10.1016/j.jbc.2022.102659

Cited by 4 publications

(1 citation statement)

References 77 publications

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“…S19) . A similar inhibitory effect on amyloid formation has recently been reported for D76N-β2-microglobulin dimers ( 72 ). This, in part, helps to rationalize the unusual dependence that has been observed between aggregation lag times and peptide concentration for GLP-1, where under specific conditions the lag times increase with increasing GLP-1 concentration ( 7 ).…”

Section: Discussionsupporting

confidence: 84%

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Brichtová¹,

Krupová²,

Bouř³

et al. 2023

Biophysical Journal

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Section: Discussionsupporting

confidence: 84%

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Brichtová¹,

Krupová²,

Bouř³

et al. 2023

Biophysical Journal

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Identification and Functional Annotation of Potential Biomarkers Associated with Thalassemia Using Machine Learning-Based Knowledge Discovery

Mora-Jimenez,

Ramírez-Benavides,

Quesada

et al. 2024

Smart Innovation, Systems and Technologies

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A Self-Consistent Molecular Mechanism of β₂-Microglobulin Aggregation

Tammara,

Das

2024

J. Phys. Chem. B

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Despite the consensus on the origin of dialysis-related amyloidosis (DRA) being β 2 -microglobulin (β 2 m) aggregation, the debate on the underlying mechanism persists because of the continuous emergence of β 2 m variant-and pH-dependent contradictory results. By characterizing the native monomeric (initiation) and aggregated fibrillar (termination) states of β 2 m via a combination of two enhanced sampling approaches, we here propose a mechanism that explains the heterogeneous behavior of wild-type (WT) and pathogenic (V27M and D76N) β 2 m variants in physiological and disease-pertinent acidic pH environments. It appears that the higher retainment of monomeric native folds at neutral pH (native-like) distinguishes pathogenic β 2 m mutants from the WT (moderate loss). However, at acidic pH, all three variants behave similarly in producing a substantial amount of partially unfolded states (conformational switch, propensity), though with different extents (WT < V27M < D76N). Whereas at the fibrillar end, all β 2 m variants display a pH-dependent protofilament separation pathway and a higher protofilament binding affinity (stability) at acidic pH, where the relative order of binding affinity (WT < V27M < D76N) remains consistent with pH modulation. Combining these observations, we conclude that β 2 m variants possibly shift from native-like aggregation to conformational switch-initiated fibrillation as the pH is altered from neutral to acidic. The combined propensity-stability approach based on the initiation and termination points of β 2 m aggregation not only assists us in deciphering the mechanism but also emphasizes the protagonistic roles of both terminal points in the overall aggregation process.

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Dimers of D76N-β2-microglobulin display potent antiamyloid aggregation activity

Cited by 4 publications

References 77 publications

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Identification and Functional Annotation of Potential Biomarkers Associated with Thalassemia Using Machine Learning-Based Knowledge Discovery

A Self-Consistent Molecular Mechanism of β₂-Microglobulin Aggregation

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Dimers of D76N-β2-microglobulin display potent antiamyloid aggregation activity

Cited by 4 publications

References 77 publications

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Glucagon-like peptide 1 aggregates into low-molecular-weight oligomers off-pathway to fibrillation

Identification and Functional Annotation of Potential Biomarkers Associated with Thalassemia Using Machine Learning-Based Knowledge Discovery

A Self-Consistent Molecular Mechanism of β2-Microglobulin Aggregation

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Product

Resources

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A Self-Consistent Molecular Mechanism of β₂-Microglobulin Aggregation