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Journal Article

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

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Bertoncini,  C. W.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Fernandez,  C. O.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Griesinger,  C.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

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Jovin,  T. M.
Department of Molecular Biology, MPI for biophysical chemistry, Max Planck Society;

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Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for biophysical chemistry, Max Planck Society;

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Citation

Bertoncini, C. W., Fernandez, C. O., Griesinger, C., Jovin, T. M., & Zweckstetter, M. (2005). Familial mutants of α-synuclein with increased neurotoxicity have a destabilized conformation. Journal of Biological Chemistry, 280, 30649-30652. Retrieved from http://www.jbc.org/cgi/content/full/280/35/30649?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=280&firstpage=30649&resourcetype=HWCIT.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0012-E826-D
Abstract
A30P and A53T mutations of the presynaptic protein α-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 α-synuclein. However, α-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. The redistribution of the ensemble of α-synuclein conformers may underlie toxic gain-of-function by fostering self-association and altered binding affinity to ligands and receptors.