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Related Experiment Videos

How evolutionary pressure against protein aggregation shaped chaperone specificity.

Frederic Rousseau1, Luis Serrano, Joost W H Schymkowitz

  • 1Switch Laboratory, Flemish Interuniversity Institute for Biotechnology, Free University Brussels, Pleinlaan 2, 1050 Brussels, Belgium. frederic.rousseau@vub.ac.be

Journal of Molecular Biology
|December 20, 2005
PubMed
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Cellular organisms rely on molecular chaperones to prevent lethal protein aggregation. Evolution minimizes aggregation by capping hydrophobic sequences with gatekeeper residues, which chaperones use to identify and bind proteins prone to aggregation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Evolutionary Biology

Background:

  • Protein aggregation poses a lethal threat to cells, necessitating control by molecular chaperones.
  • Unfolded proteins during expression and translocation are highly susceptible to non-native interactions and aggregation.

Purpose of the Study:

  • To analyze protein aggregation propensities across 28 complete proteomes using the TANGO algorithm.
  • To investigate evolutionary strategies for minimizing protein aggregation.
  • To understand how molecular chaperones recognize and bind aggregation-prone substrates.

Main Methods:

  • Utilized TANGO, a statistical mechanics algorithm, for predicting protein aggregation.
  • Analyzed aggregation propensities in 28 complete proteomes.

Related Experiment Videos

  • Examined the role of specific amino acid residues (arginine, lysine, proline) as aggregation gatekeepers.

    • Main Results:

    • 10-20% of residues in proteomes are within aggregating segments, representing a lower limit for globular protein aggregation.
    • Evolution minimizes aggregation by reducing strongly aggregating sequences and capping them with gatekeeper residues (arginine, lysine, proline).
    • Chaperone substrate specificity is dictated by these gatekeepers, enabling selective binding of aggregation-prone hydrophobic sequences.

    Conclusions:

    • Evolutionary pressure actively suppresses protein aggregation through sequence design and gatekeeper residues.
    • Gatekeeper residues (arginine, lysine, proline) are crucial for chaperones to selectively bind and manage aggregation-prone proteins.
    • Chaperone-substrate interactions are finely tuned by evolutionarily selected gatekeepers, ensuring efficient recognition of potentially aggregating proteins.