Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation.

BERTONCINI, C.; CLAUDIO OSCAR FERNANDEZ; GRIESINGER, C.; JOVIN, T.; ZWECKSTETTER, M.

JOURNAL OF BIOLOGICAL CHEMISTRY

Año: 2005 vol. 280 p. 30649 - 30652

0021-9258

A30P and A53T mutations of the presynaptic protein a-synuclein are associated with familial forms of Parkinson?s disease. NMR spectroscopy demonstrates that Parkinsonism-linked mutations greatly perturb specific tertiary interactions essential for the native state of a-synuclein. However, a-synuclein is not completely unfolded, but exhibits structural fluctuations on the time scale of secondary structure formation, and loses its native conformation gradually when protein stability decreases, a characteristic property of downhill folding proteins. The redistribution of the ensemble of a-synuclein conformers may underlie toxic gain-of-function by fostering self-association and altered binding affinity to ligands and receptors.