Acetylation Rather than H50Q Mutation Impacts the Kinetics of Cu(II) Binding to α-Synuclein
| Autor: | Xiangyu Teng, Alena Sheveleva, Floriana Tuna, Keith R. Willison, Liming Ying |
|---|---|
| Přispěvatelé: | The Leverhulme Trust, Biotechnology and Biological Sciences Research Council (BBSRC) |
| Rok vydání: | 2021 |
| Předmět: |
IONS
inorganic chemicals Kinetics Physics Atomic Molecular & Chemical medicine.disease_cause COPPER(II) BINDING chemistry.chemical_compound α-synuclein medicine SWITCH Humans 0307 Theoretical and Computational Chemistry Physical and Theoretical Chemistry Copper levels FRAGMENTS AFFINITY Coordination geometry 0306 Physical Chemistry (incl. Structural) COORDINATION Mutation Science & Technology coordination modes Chemical Physics Binding Sites Chemistry Physical Physics Wild type SITE Acetylation Glutathione fluorescence spectroscopy AGGREGATION Atomic and Molecular Physics and Optics Chemistry INSIGHTS chemistry Physical Sciences 0202 Atomic Molecular Nuclear Particle and Plasma Physics Biophysics alpha-Synuclein α synuclein BIOINORGANIC CHEMISTRY Copper |
| Zdroj: | Chemphyschem : a European journal of chemical physics and physical chemistry. 22(23) |
| ISSN: | 1439-7641 |
| Popis: | The interaction between α-synuclein (αSyn) and Cu2+ has been suggested to be closely linked to brain copper homeostasis. Disruption of copper levels could induce misfolding and aggregation of αSyn, and thus contribute to the progression of Parkinson's disease (PD). Understanding the molecular mechanism of αSyn-Cu2+ interaction is important but there still exist controversies in Cu2+ coordination geometry with αSyn. Herein, we find that the pathological H50Q mutation has no impact on the kinetics of Cu2+ binding to the high-affinity site of wild type αSyn (WT-αSyn), indicating the non-involvement of His50 in high-affinity Cu2+ binding to WT-αSyn. In contrast, the physiological N-terminally acetylated αSyn (NAc-αSyn) displays several orders of magnitude weaker Cu2+ binding affinity than WT-αSyn. Cu2+ coordination mode to NAc-αSyn has also been proposed based on EPR spectrum. In addition, we find that Cu2+ coordinated WT-αSyn is reduction-active in the presence of GSH, but essentially inactive towards ascorbate. Our work provides new insights into αSyn-Cu2+ interaction, which may help understand the multifaceted normal functions of αSyn as well as pathological consequences of αSyn aggregation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text