Familial mutants of alpha-synuclein with increased neurotoxicity have a destabilized conformation.
A30P and A53T mutations of the presynaptic protein alpha-synuclein are associated with familial forms of Parkinson disease. NMR spectroscopy demonstrates that Parkinsonism-linked mutations greatly perturb specific tertiary interactions essential for the native state of alpha-synuclein. However, alpha-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 alpha-synuclein conformers may underlie toxic gain-of-function by fostering self-association and altered binding affinity to ligands and receptors.
Bertoncini
Carlos W
CW
Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Fernandez
Claudio O
CO
Griesinger
Christian
C
Jovin
Thomas M
TM
Zweckstetter
Markus
M
D000595:Amino Acid Sequence; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D019906:Nuclear Magnetic Resonance, Biomolecular; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism; D017510:Protein Folding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D051843:Synucleins; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein