Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90

Edgar E. Boczek, Lasse G. Reefschläger, Marco Dehling, Tobias J. Struller, Elisabeth Häusler, Andreas Seidl, Ville R.I. Kaila, Johannes Buchner

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency. Consistent with in vivo results, we find that Hsp90 does not influence the almost identical c-Src kinase. To explain these findings, we designed Src kinase chimeras that gradually transform c-Src into v-Src and show that their Hsp90 dependence correlates with compactness and folding cooperativity. Molecular dynamics simulations and hydrogen/deuterium exchange of Hsp90-dependent Src kinase variants further reveal increased transitions between inactive and active states and exposure of specific kinase regions. Thus, Hsp90 shifts an ensemble of conformations of v-Src toward high activity states that would otherwise be metastable and poorly populated.

Original languageEnglish
Pages (from-to)E3189-E3198
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number25
StatePublished - 23 Jun 2015
Externally publishedYes


  • Cdc37
  • Chaperone mechanism
  • Conformational ensembles
  • Kinase activation
  • Metastable states


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