Polyglutamine aggregation nucleation: Thermodynamics of a highly unfavorable protein folding reaction

  • Bhattacharyya A
  • Thakur A
  • Wetzel R
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Abstract

Polyglutamine (polyGln) aggregation is implicated in the disease progression of Huntington's disease and other expanded CAG repeat diseases. PolyGln aggregation in vitro follows a simple nucleated growth polymerization pathway without apparent complications such as populated intermediates, alternative assembly pathways, or secondary nucleation phenomena. Previous analysis of the aggregation of simple polyGln peptides revealed that the critical nucleus (the number of monomeric units involved in the formation of an energetically unfavorable aggregation nucleus) is equal to one, suggesting that polyGln nucleation can be viewed as an unfavorable protein folding reaction. We provide here a method for experimentally determining the number of elongation growth sites per unit weight for any polyGln aggregate preparation, a key parameter required for completion of the nucleation kinetics analysis and determination of the thermodynamics of nucleation. We find that, for the polyGln peptide Q(47), the second-order rate constant for fibril elongation is 11,400 liters/mol per s, whereas K(n*)), the equilibrium constant for nucleation of aggregation, is remarkably small, equal to 2.6 x 10(-9). The latter value corresponds to a free energy of nucleus formation of +12.2 kcal/mol, a value consistent with a highly unfavorable folding reaction. The methods introduced here should allow further analysis of the energetics of polyGln nucleus formation and accurate comparisons of the seeding capabilities of different fibril preparations, a task of increasing importance in the amyloid field.

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Authors

  • A. M. Bhattacharyya

  • A. K. Thakur

  • R. Wetzel

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