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Related Experiment Video

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Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
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Hsp90 promotes kinase evolution.

Jennifer Lachowiec1, Tzitziki Lemus2, Elhanan Borenstein3

  • 1Molecular and Cellular Biology Program, University of Washington Department of Genome Sciences, University of Washington.

Molecular Biology and Evolution
|September 24, 2014
PubMed
Summary
This summary is machine-generated.

Heat-shock protein 90 (Hsp90) client status promotes kinase evolution by enabling genetic variation accumulation. This chaperone

Keywords:
Hsp90capacitorevolutiongene familykinaserelaxed selection

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Area of Science:

  • Molecular biology
  • Evolutionary biology
  • Biochemistry

Background:

  • Heat-shock protein 90 (Hsp90) is a molecular chaperone.
  • Hsp90 stabilizes client proteins, including kinases, potentially facilitating mutation accumulation.
  • The capacitor hypothesis suggests Hsp90 clients accumulate mutations due to chaperone support.

Purpose of the Study:

  • To investigate if Hsp90 client status influences the evolutionary rate of protein kinases.
  • To determine if Hsp90's effect is independent of gene expression and protein connectivity.
  • To examine the evolutionary dynamics and conservation of Hsp90 client status.

Main Methods:

  • Comparative analysis of evolutionary rates between Hsp90 clients and nonclients in the human protein kinase superfamily.
  • Statistical assessment of Hsp90 client status's impact on evolutionary rate, controlling for gene expression and protein connectivity.
  • Analysis of nucleotide diversity and damaging variation in human Hsp90 client kinases.
  • Phylogenetic analysis to infer the evolutionary history of Hsp90 client status within the protein kinase superfamily.

Main Results:

  • Hsp90 client status significantly increases evolutionary rate in protein kinases, independent of gene expression and connectivity.
  • This effect is characterized by relaxed purifying selection across mammals.
  • Hsp90 client kinases exhibit higher nucleotide diversity and harbor more damaging genetic variations in humans.
  • Hsp90 client status is generally conserved among related kinases, contrary to expectations of high dynamism.

Conclusions:

  • Hsp90 client status facilitates the accumulation of genetic variation in kinases, supporting the capacitor hypothesis.
  • Hsp90 has played a significant role in shaping the evolutionary trajectory of the protein kinase superfamily.
  • The conserved nature of Hsp90 client status suggests a stable evolutionary role rather than a transient one.