Copper Induced Radical Dimerization of α-Synuclein Requires Histidine
| Autor: | Heather R. Lucas, Madeleine K Crozier, Dinendra L Abeyawardhane, Ricardo D. Fernández, Denver R. Heitger, Julia C Wolver |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Free Radicals Protein Conformation medicine.disease_cause Biochemistry Catalysis 03 medical and health sciences Residue (chemistry) Colloid and Surface Chemistry Protein structure Coordination Complexes medicine Humans Histidine Amino Acid Sequence Peptide sequence Mutation Chemistry Intermolecular force Acetylation General Chemistry Oxygen 030104 developmental biology Intramolecular force alpha-Synuclein Biophysics Tyrosine Protein Multimerization Copper |
| Zdroj: | Journal of the American Chemical Society. 140:17086-17094 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.8b08947 |
| Popis: | Aggregation of the neuronal protein α-synuclein (αS) is a critical factor in the pathogenesis of Parkinson’s disease. Analytical methods to detect post-translational modifications of αS are under development, yet the mechanistic underpinnings of biomarkers like dityrosine formation within αS have yet to be established. In our work, we demonstrate that CuI-bound N-terminally acetylated αS (NAcαS) activates O2 resulting in both intermolecular dityrosine cross-linking within the fibrillar core as well as intramolecular cross-linking within the C-terminal region. Substitution of the H50 residue with a disease relevant Q mutation abolishes intermolecular dityrosine cross-linking and limits the CuI/O2 promoted cross-linking to the C-terminal region. Such a dramatic change in reaction behavior establishes a previously unidentified role for H50 in facilitating intermolecular cross-linking. Involvement of H50 in the reaction profile implies that long-range histidine coordination with the upstream CuI coordination ... |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|