title: Hsp90 dependence of a kinase is determined by its conformational landscape.
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.
authors.affiliation: Department Chemie, Technische Universität München, Lichtenbergstraße 4, D-85748, Garching, Germany.|Soft Matter Research Center and Department of Chemistry, Zhejiang University, 310027, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department Chemie, Technische Universität München, Lichtenbergstraße 4, D-85748, Garching, Germany.|Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstraße 108, 01307 Dresden, Germany.
authors.forename: Edgar E
authors.initials: EE
authors.lastname: Boczek
authors.affiliation: Soft Matter Research Center and Department of Chemistry, Zhejiang University, 310027, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department Chemie, Technische Universität München, Lichtenbergstraße 4, D-85748, Garching, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Buchner
authors.affiliation: Department Chemie, Technische Universität München, Lichtenbergstraße 4, D-85748, Garching, Germany.
authors.forename: Ville R I
authors.initials: VR
authors.lastname: Kaila
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015688:Oncogene Protein pp60(v-src) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D019061:src-Family Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D050505:Mutant Proteins; D000255:Adenosine Triphosphate; D000081247:CSK Tyrosine-Protein Kinase; D015688:Oncogene Protein pp60(v-src); D019061:src-Family Kinases; C000631346:CSK protein, human