Epigallocatechin-3-gallate Inhibits Cu(II)-Induced β-2-Microglobulin Amyloid Formation by Binding to the Edge of Its β-Sheets
| Autor: | Tyler M. Marcinko, Thomas M. Drews, Richard W. Vachet, Tianying Liu |
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| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Amyloid Dimer Amyloidogenic Proteins Biochemistry complex mixtures Catechin Mass Spectrometry Article 03 medical and health sciences chemistry.chemical_compound Protein structure Tetramer medicine Humans 0303 health sciences Chemistry Beta-2 microglobulin 030302 biochemistry & molecular biology food and beverages Amyloidosis Monomer Mechanism of action Biophysics Chromatography Gel Protein Conformation beta-Strand medicine.symptom Protein Multimerization beta 2-Microglobulin Copper |
| Zdroj: | Biochemistry |
| ISSN: | 1520-4995 |
| Popis: | Epigallocatechin-3-gallate (EGCG) is a catechin found in green tea that can inhibit the amyloid formation of a wide variety of proteins. EGCG’s ability to prevent or re-direct the amyloid formation of so many proteins may reflect a common mechanism of action, and thus greater molecular-level insight into how it exerts its effect could have broad implications. Here, we investigate the molecular details of EGCG’s inhibition of the protein β−2-microglobulin (β2m), which forms amyloids in patients undergoing long-term dialysis treatment. Using size-exclusion chromatography and a collection of mass spectrometry-based techniques, we find that EGCG prevents Cu(II)-induced β2m amyloid formation by diverting the normal progression of pre-amyloid oligomers toward the formation of spherical, re-dissolvable aggregates. EGCG exerts its effect by binding with micromolar affinity (Kd ≈ 5 μM) to the β2m monomer on the edge of two β-sheets near the N-terminus. This interaction destabilizes the pre-amyloid dimer and prevents the formation of a tetramer species previously shown to be essential for Cu(II)-induced β2m amyloid formation. EGCG’s binding at the edge of the β-sheets in β2m is consistent with a previous hypothesis that EGCG generally prevents amyloid formation by binding cross-β-sheet aggregation intermediates. |
| Databáze: | OpenAIRE |
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