Client Proteins and Small Molecule Inhibitors Display Distinct Binding Preferences for Constitutive and Stress-Induced HSP90 Isoforms and Their Conformationally Restricted Mutants

• DOI: 10.1371/journal.pone.0141786
• Publication Date: 2015-10-30T18:28:23Z
• Authors: Thomas L. Prince; Toshiki Kijima; Manabu Tatokoro; Sunmin Lee; Shinji Tsutsumi; Kendrick Yim; Candy Rivas; Sylvia Alarcon; Harvey Schwartz; Kofi Khamit-Kush; Bradley T. Scroggins; Kristin Beebe; Jane B. Trepel; Len Neckers
• Keywords: Geldanamycin; Hsp90 inhibitor

The two cytosolic/nuclear isoforms of the molecular chaperone HSP90, stress-inducible HSP90α and constitutively expressed HSP90β, fold, assemble maintain three-dimensional structure numerous client proteins. Because many HSP90 clients are important in cancer, several inhibitors have been evaluated clinic. However, little is known concerning possible unique isoform or conformational preferences either individual inhibitors. In this report, we compare relative interaction strength both HSP90β with transcription factors HSF1 HIF1α, kinases ERBB2 MET, E3-ubiquitin ligases KEAP1 RHOBTB2, geldanamycin ganetespib. We observed unexpected differences drug for isoforms, binding each protein greater apparent affinity compared to while bound inhibitor HSP90α. Stable was associated reduced activity. Using a defined set mutants, found that some interact strongly single, ATP-stabilized conformation, only transiently populated during dynamic cycle, other equally multiple conformations. These data suggest different functional requirements among clientele that, clients, likely be ATP-independent. Lastly, examined, although sharing same site, were differentially able access distinct states.