Hsp90 dependence of a kinase is determined by its conformational landscape

Qi Luo, Edgar E. Boczek, Qi Wang, Johannes Buchner, Ville R.I. Kaila

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Heat shock protein 90 (Hsp90) is an abundant molecular chaperone, involved in the folding and activation of 60% of the human kinome. The oncogenic tyrosine kinase v-Src is one of the most stringent client proteins of Hsp90, whereas its almost identical homolog c-Src is only weakly affected by the chaperone. Here, we perform atomistic molecular simulations and in vitro kinase assays to explore the mechanistic differences in the activation of v-Src and c-Src. While activation in c-Src is strictly controlled by ATP-binding and phosphorylation, we find that activating conformational transitions are spontaneously sampled in Hsp90-dependent Src mutants. Phosphorylation results in an enrichment of the active conformation and in an increased affinity for Hsp90. Thus, the conformational landscape of the mutated kinase is reshaped by a broken "control switch", resulting in perturbations of long-range electrostatics, higher activity and increased Hsp90-dependence.

Original languageEnglish
Article number43996
JournalScientific Reports
Volume7
DOIs
StatePublished - 14 Mar 2017

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