Grabenauer, Megan and Bernstein, Summer L. and Lee, Jennifer C. and Wyttenbach, Thomas and Dupuis, Nicholas F. and Gray, Harry B. and Winkler, Jay R. and Bowers, Michael T. (2008) Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants. Journal of Physical Chemistry B, 112 (35). pp. 11147-11154.
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Aggregation of alpha-synuclein (alpha-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 alpha-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 A2 (-10 charge state) down to 1430 A2 (-6 charge state)). We conclude that spermine increases the aggregation rate of alpha-syn by inducing a collapsed conformation, which then proceeds to form aggregates.
|Additional Information:||Copyright 2008 American Chemical Society. Received: February 8, 2008; Revised Manuscript Received: June 11, 2008. Web Release Date: August 9, 2008. We thank Professor Joe Loo for suggesting the experiments with spermine and Dr. Catherine J. Carpenter for help with preparation of the figures. Support from the National Science Foundation (grant CHE-0503728 (M.T.B.)), National Institutes of Health (grant GM068461 (J.R.W.)), the Ellison Medical Foundation (Senior Scholar Award in Aging to H.B.G.), and the Arnold and Mabel Beckman Foundation (J.C.L.) are gratefully acknowledged.|
|Subjects:||Biomedical Science > Nanotechnology for human health|
Analytical Science > Beam methods
|Deposited By:||Lesley Tobin|
|Deposited On:||04 Dec 2008 16:11|
|Last Modified:||09 Feb 2009 17:15|
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