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Analysis of conformational determinants underlying HSP90-kinase interaction

Rama Krishna Kancha1, Natalie Bartosch, Justus Duyster

  • 1Department Medicine I, University Medical Center Freiburg, Freiburg, Germany.

Plos One
|July 12, 2013
PubMed

Insights

Heat shock protein 90 (HSP90) stabilizes oncogenic kinases. Active ERBB2 interacts with HSP90 for degradation, while inactive ERBB2 does not. Kinase inhibitor binding affects HSP90 interactions differently across various kinases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Heat shock protein 90 (HSP90) is crucial for stabilizing oncogenic tyrosine kinases, making it a promising cancer therapeutic target.
  • The precise molecular mechanisms governing the interaction between HSP90 and its client kinases remain incompletely understood.

Purpose of the Study:

  • To investigate the relationship between kinase conformation and HSP90 interaction.
  • To determine how kinase inhibitors affect the HSP90 chaperone-client kinase complex.
  • To elucidate the differential stability of active kinase conformations.

Main Methods:

  • Utilized various kinase inhibitors to probe interactions.
  • Analyzed the binding of ERBB2 to HSP90 in different conformational states.
  • Examined HSP90 interactions with BCR-ABL and FLT3-ITD in the presence of inhibitors.

Main Results:

  • Inactive ERBB2 does not interact with HSP90 and is resistant to HSP90 inhibitor-induced degradation.
  • Active ERBB2 readily interacts with HSP90 and undergoes degradation upon HSP90 inhibition.
  • HSP90-kinase interactions are disrupted by inhibitors for BCR-ABL and FLT3-ITD, regardless of the inhibited conformation.
  • The stability of the active kinase conformation varies significantly among different kinases.

Conclusions:

  • Kinase conformation dictates HSP90 interaction and subsequent degradation.
  • HSP90 inhibitor efficacy is dependent on both kinase conformation and specific kinase identity.
  • Understanding these interactions is key to developing more effective targeted cancer therapies.

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