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

RODOLFO M. RASIA; CARLOS W. BERTONCINI; DEREK MARSH; WOLFGANG HOYER; DMITRY CHERNY; MARKUS ZWECKSTETTER; CHRISTIAN GRIESINGER; THOMAS M. JOVIN; CLAUDIO O. FERNANDEZ

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

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2005 vol. 102 p. 4294 - 4299

0027-8424

The aggregation of alpha-synuclein (AS) is characteristic of Parkinson´s disease and other neurodegenerative synucleinopathies. We demonstrate here that Cu(II) ions are effective in accelerating AS aggregation at physiologically relevant concentrations without altering the resultant fibrillar structures. By using numerous 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 His-50 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 AS-Cu(II) complexes reveals the existence of conformational restrictions in the native state of the protein. The metallobiology of Cu(II) in Parkinson´s disease is discussed by a comparative analysis with other Cu(II)-binding proteins involved in neurodegenerative disorders.