• Article

Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants

Aggregation of α-synuclein (α-syn), a protein implicated in Parkinson’s disease (PD), is believed to progress through formation of a partially folded intermediate. Using nanoelectrospray ionization (nano-ESI) mass spectrometry combined with ion mobility measurements we found evidence for a highly compact partially folded family of structures for α-syn and its disease-related A53T mutant with net charges of −6, −7, and −8. For the other early onset PD mutant, A30P, this highly compact population was only evident when the protein had a net charge of −6. When bound to spermine near physiologic pH, all three proteins underwent a charge reduction from the favored solution charge state of −10 to a net charge of −6. This charge reduction is accompanied by a dramatic size reduction of about a factor of 2 (cross section of 2600 Å2 (−10 charge state) down to 1430 Å2 (−6 charge state)). We conclude that spermine increases the aggregation rate of α-syn by inducing a collapsed conformation, which then proceeds to form aggregates.

Citation

Grabenauer, M., Bernstein, S., Lee, J., Wyttenbach, T., Dupuis, N., Gray, H., ... Bowers, M. (2008). Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants. The Journal of Physical Chemistry, 112(35), 11147-11154. https://doi.org/10.1021/jp801175w

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