Inorganic Chemistry
Article
̌
́
(c) Meloni, G.; Vasak, M. Redox activity of α-synuclein−Cu is
silenced by Zn7-metallothionein-3. Free Radical Biol. Med. 2011, 50
(11), 1471−1479.
metal ions in the amyloid assembly, redox chemistry, and
cytotoxicity of αSyn and other amyloidogenic proteins.
(6) (a) Abeyawardhane, D. L.; Fernandez, R. D.; Heitger, D. R.;
Crozier, M. K.; Wolver, J. C.; Lucas, H. R. Copper Induced Radical
Dimerization of alpha-Synuclein Requires Histidine. J. Am. Chem. Soc.
2018, 140 (49), 17086−17094. (b) Al-Hilaly, Y. K.; Biasetti, L.;
Blakeman, B. J. F.; Pollack, S. J.; Zibaee, S.; Abdul-Sada, A.; Thorpe, J.
R.; Xue, W. F.; Serpell, L. C. The involvement of dityrosine
crosslinking in alpha-synuclein assembly and deposition in Lewy
Bodies in Parkinson’s disease. Sci. Rep. 2016, 6, 39171. (c) Gu, M.;
Bode, D. C.; Viles, J. H. Copper Redox Cycling Inhibits A beta Fibre
Formation and Promotes Fibre Fragmentation, while Generating a
Dityrosine A beta Dimer. Sci. Rep. 2018, 8, 16190.
(7) (a) Borghi, R.; Marchese, R.; Negro, A.; Marinelli, L.; Forloni,
G.; Zaccheo, D.; Abbruzzese, G.; Tabaton, M. Full length alpha-
synuclein is present in cerebrospinal fluid from Parkinson’s disease
and normal subjects. Neurosci. Lett. 2000, 287 (1), 65−67. (b) Lee, S.
J. Origins and effects of extracellular alpha-synuclein: Implications in
Parkinson’s disease. J. Mol. Neurosci. 2008, 34 (1), 17−22.
(8) Zhang, H. Y.; Griggs, A.; Rochet, J. C.; Stanciu, L. A. In Vitro
Study of alpha-Synuclein Protofibrils by Cryo-EM Suggests a Cu2+-
Dependent Aggregation Pathway. Biophys. J. 2013, 104 (12), 2706−
2713.
(9) (a) Uversky, V. N.; Li, J.; Fink, A. L. Metal-triggered Structural
Transformations, Aggregation, and Fibrillation of Human α-
Synuclein: A POSSIBLE MOLECULAR LINK BETWEEN PAR-
KINSON′S DISEASE AND HEAVY METAL EXPOSURE. J. Biol.
Chem. 2001, 276 (47), 44284−44296. (b) Wright, J. A.; Wang, X.;
Brown, D. R. Unique copper-induced oligomers mediate alpha-
synuclein toxicity. FASEB J. 2009, 23 (8), 2384−2393. (c) Choi, T.
S.; Lee, J.; Han, J. Y.; Jung, B. C.; Wongkongkathep, P.; Loo, J. A.;
Lee, M. J.; Kim, H. I. Supramolecular Modulation of Structural
Polymorphism in Pathogenic -Synuclein Fibrils Using Copper(II)
Coordination. Angew. Chem., Int. Ed. 2018, 57 (12), 3099−3103.
(10) (a) Rasia, R. M.; Bertoncini, C. W.; Marsh, D.; Hoyer, W.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
■
S
Spectra showing stoichiometry, metal ion binding, pH
dependence, concentration dependence (PDF)
AUTHOR INFORMATION
Corresponding Author
ORCID
■
Author Contributions
∥Authors have contributed equally to this manuscript.
Funding
We are thankful for the support of the China Scholarship
Council and the BBSRC; Grant No. BB/M023877/1.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Polymeropoulos, M. H.; Lavedan, C.; Leroy, E.; Ide, S. E.;
Dehejia, A.; Dutra, A.; Pike, B.; Root, H.; Rubenstein, J.; Boyer, R.;
Stenroos, E. S.; Chandrasekharappa, S.; Athanassiadou, A.;
Papapetropoulos, T.; Johnson, W. G.; Lazzarini, A. M.; Duvoisin, R.
C.; DiIorio, G.; Golbe, L. I.; Nussbaum, R. L. Mutation in the alpha-
synuclein gene identified in families with Parkinson’s disease. Science
1997, 276 (5321), 2045−2047. (b) Kruger, R.; Kuhn, W.; Muller, T.;
Woitalla, D.; Graeber, M.; Kosel, S.; Przuntek, H.; Epplen, J. T.;
Schols, L.; Riess, O. Ala30Pro mutation in the gene encoding alpha-
synuclein in Parkinson’s disease. Nat. Genet. 1998, 18 (2), 106−108.
(c) Appel-Cresswell, S.; Vilarino-Guell, C.; Encarnacion, M.;
Sherman, H.; Yu, I.; Shah, B.; Weir, D.; Thompson, C.; Szu-Tu, C.;
Trinh, J.; Aasly, J. O.; Rajput, A.; Rajput, A. H.; Stoessl, A. J.; Farrer,
M. J. Alpha-synuclein p.H50Q, a novel pathogenic mutation for
Parkinson’s disease. Mov. Disord. 2013, 28 (6), 811−813.
(2) Pall, H. S.; Blake, D. R.; Gutteridge, J. M.; Williams, A. C.;
Lunec, J.; Hall, M.; Taylor, A. RAISED CEREBROSPINAL-FLUID
COPPER CONCENTRATION IN PARKINSON’S DISEASE.
Lancet 1987, 330 (8553), 238−241.
(3) Gorell, J.; Johnson, C.; Rybicki, B.; Peterson, E.; Kortsha, G.;
Brown, G.; Richardson, R. Occupational exposure to manganese,
copper, lead, iron, mercury and zinc and the risk of Parkinson’s
disease. Neurotoxicology 1998, 20 (2−3), 239−247.
́
Cherny, D.; Zweckstetter, M.; Griesinger, C.; Jovin, T. M.; Fernandez,
C. O. Structural characterization of copper(II) binding to α-synuclein:
Insights into the bioinorganic chemistry of Parkinson’s disease. Proc.
Natl. Acad. Sci. U. S. A. 2005, 102 (12), 4294−4299. (b) Binolfi, A.;
Rasia, R. M.; Bertoncini, C. W.; Ceolin, M.; Zweckstetter, M.;
Griesinger, C.; Jovin, T. M.; Fernandez, C. O. Interaction of alpha-
synuclein with divalent metal ions reveals key differences: A link
between structure, binding specificity and fibrillation enhancement. J.
Am. Chem. Soc. 2006, 128 (30), 9893−9901. (c) Abeyawardhane, D.
L.; Heitger, D. R.; Fernandez, R. D.; Forney, A. K.; Lucas, H. R. C-
Terminal Cu-II Coordination to alpha-Synuclein Enhances Aggrega-
tion. ACS Chem. Neurosci. 2019, 10 (3), 1402−1410.
(11) Viles, J. H. Metal ions and amyloid fiber formation in
neurodegenerative diseases. Copper, zinc and iron in Alzheimer’s,
Parkinson’s and prion diseases. Coord. Chem. Rev. 2012, 256 (19−20),
2271−2284.
(12) (a) Martin, R. B. Optical properties of transition metal ion
complexes of amino acids and peptides. Metal ions in biological systems
1974, 1, 129−156. (b) Stanyon, H. F.; Cong, X. J.; Chen, Y.;
Shahidullah, N.; Rossetti, G.; Dreyer, J.; Papamokos, G.; Carloni, P.;
Viles, J. H. Developing predictive rules for coordination geometry
from visible circular dichroism of copper(II) and nickel(II) ions in
histidine and amide main-chain complexes. FEBS J. 2014, 281 (17),
3945−3954. (c) Klewpatinond, M.; Viles, J. H. Empirical rules for
rationalising visible circular dichroism of Cu(2+) and Ni(2+)
histidine complexes: Applications to the prion protein. FEBS Lett.
2007, 581 (7), 1430−1434.
(4) (a) Binolfi, A.; Valiente-Gabioud, A. A.; Duran, R.; Zweckstetter,
M.; Griesinger, C.; Fernandez, C. O. Exploring the Structural Details
of Cu(I) Binding to alpha-Synuclein by NMR Spectroscopy. J. Am.
Chem. Soc. 2011, 133 (2), 194−196. (b) Binolfi, A.; Quintanar, L.;
́
Bertoncini, C. W.; Griesinger, C.; Fernandez, C. O. Bioinorganic
chemistry of copper coordination to alpha-synuclein: Relevance to
Parkinson’s disease. Coord. Chem. Rev. 2012, 256 (19−20), 2188−
2201. (c) Valensin, D.; Dell’Acqua, S.; Kozlowski, H.; Casella, L.
Coordination and redox properties of copper interaction with alpha-
synuclein. J. Inorg. Biochem. 2016, 163, 292−300.
(13) (a) Klewpatinond, M.; Davies, P.; Bowen, S.; Brown, D. R.;
Viles, J. H. Deconvoluting the Cu2+ Binding Modes of Full-length
Prion Protein. J. Biol. Chem. 2008, 283 (4), 1870−1881. (b) Viles, J.
H.; Cohen, F. E.; Prusiner, S. B.; Goodin, D. B.; Wright, P. E.; Dyson,
H. J. Copper binding to the prion protein: Structural implications of
four identical cooperative binding sites. Proc. Natl. Acad. Sci. U. S. A.
(5) (a) Wang, C.; Liu, L.; Zhang, L.; Peng, Y.; Zhou, F. Redox
Reactions of the α-Synuclein−Cu2+ Complex and Their Effects on
Neuronal Cell Viability. Biochemistry 2010, 49 (37), 8134−8142.
(b) Davies, P.; Wang, X.; Sarell, C. J.; Drewett, A.; Marken, F.; Viles,
J. H.; Brown, D. R. The Synucleins Are a Family of Redox-Active
Copper Binding Proteins. Biochemistry 2011, 50 (1), 37−47.
I
Inorg. Chem. XXXX, XXX, XXX−XXX