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

J Phys Chem B. 2008 Sep 4;112(35):11147-54. doi: 10.1021/jp801175w. Epub 2008 Aug 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Mass Spectrometry
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism*
  • Protein Binding
  • Spermine / metabolism*
  • Time Factors
  • alpha-Synuclein / chemistry
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism*

Substances

  • Mutant Proteins
  • alpha-Synuclein
  • Spermine