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