Structural characterization of Copper (II) binding to alpha-synuclein : Insights into the bioinorganic chemistry of Parkinson?s disease

RASIA, RM, BERTONCINI CW, MARSH D, HOYER W, CHERNY D, ZWECKSTETTER M, GRIESINGER C, JOVIN TM, FERNÁNDEZ CO

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Año: 2005 vol. 102 p. 4294 - 4299

0027-8424

The aggregation of a-synuclein is characteristic of Parkinson?s disease (PD) and other neurodegenerative synucleinopathies. We demonstrate here that Cu(II) ions are effective in accelerating a-synuclein aggregation at physiologically relevant concentrations without altering the resultant fibrillar structures. Using a battery of spectroscopic techniques (absorption, CD, EPR and NMR) we have located the primary binding for Cu(II) to a specific site in the N-terminus, involving His50 as the anchoring residue and other nitrogen/oxygen donor atoms in a square planar or distorted tetragonal geometry. The carboxylate-rich C-terminus, originally thought to drive copper binding, is able to coordinate a second Cu(II) equivalent, albeit with a 300-fold reduced affinity. The NMR analysis of a-synuclein/Cu(II) complexes reveals the existence of conformational restrictions in the native state of the protein. The metallobiology of Cu(II) in PD is discussed via a comparative analysis with other Cu(II) binding proteins involved in neurodegenerative disorders.