title: Spermine binding to Parkinson's protein alpha-synuclein and its disease-related A30P and A53T mutants.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Grabenauer
authors.forename: Summer L
authors.initials: SL
authors.lastname: Bernstein
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Wyttenbach
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dupuis
authors.forename: Harry B
authors.initials: HB
authors.lastname: Gray
authors.forename: Jay R
authors.initials: JR
authors.lastname: Winkler
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D013058:Mass Spectrometry; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D013096:Spermine / Q000378:metabolism*; D013997:Time Factors; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D051844:alpha-Synuclein; D013096:Spermine