Time scale of protein aggregation dictated by liquid-liquid demixing

S. M. Vaiana, M. B. Palma-Vittorelli, M. U. Palma

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

The growing impact of protein aggregation pathologies, together with the current high need for extensive information on protein structures are focusing much interest on the physics underlying the nucleation and growth of protein aggregates and crystals. Sickle Cell Hemoglobin (HbS), a point-mutant form of normal human Hemoglobin (HbA), is the first recognized and best-studied case of pathologically aggregating protein. Here we reanalyze kinetic data on nucleation of deoxy-HbS aggregates by referring them to the (concentration-dependent) temperature Ts characterizing the occurrence of the phase transition of liquid-liquid demixing (LLD) of the solution. In this way, and by appropriate scaling of kinetic data at different concentrations, so as to normalize their spans, the apparently disparate sets of data are seen to fall on a master curve. Expressing the master curve vs. the parameter ε = (T - Ts) / Ts, familiar from phase transition theory, allows eliciting the role of anomalously large concentration fluctuations associated with the LLD phase transition and also allows decoupling quantitatively the role of such fluctuations from that of microscopic, inter-protein interactions leading to nucleation. Referring to E shows how in a narrow temperature span, that is at T≈Ts, nucleation kinetics can undergo orders-of-magnitude changes, unexpected in terms of ordinary chemical kinetics. The same is true for similarly small changes of other parameters (pH, salts, precipitants), capable of altering Ts. and consequently ε. This offers the rationale for understanding how apparently minor changes of parameters can dramatically affect protein aggregation and related diseases.

Original languageEnglish (US)
Pages (from-to)147-153
Number of pages7
JournalProteins: Structure, Function and Genetics
Volume51
Issue number1
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

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Keywords

  • Aggregation kinetics
  • Amyloids
  • Fibrils
  • Neurodegenerative diseases
  • Nucleation
  • Prions
  • Protein crystallization
  • Protein deposit
  • Protein fibers
  • Spinodal

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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