title: Hsp90 is cleaved by reactive oxygen species at a highly conserved N-terminal amino acid motif.
abstract: Hsp90 is an essential chaperone that is necessary for the folding, stability and activity of numerous proteins. In this study, we demonstrate that free radicals formed during oxidative stress conditions can cleave Hsp90. This cleavage occurs through a Fenton reaction which requires the presence of redox-active iron. As a result of the cleavage, we observed a disruption of the chaperoning function of Hsp90 and the degradation of its client proteins, for example, Bcr-Abl, RIP, c-Raf, NEMO and hTert. Formation of Hsp90 protein radicals on exposure to oxidative stress was confirmed by immuno-spin trapping. Using a proteomic analysis, we determined that the cleavage occurs in a conserved motif of the N-terminal nucleotide binding site, between Ile-126 and Gly-127 in Hsp90β, and between Ile-131 and Gly-132 in Hsp90α. Given the importance of Hsp90 in diverse biological functions, these findings shed new light on how oxidative stress can affect cellular homeostasis.
authors: Louvain Drug Research Institute, Université catholique de Louvain (UCL), Brussels, Belgium.
authors: Raphaël
authors: R
authors: Beck
authors: Nicolas
authors: N
authors: Dejeans
authors: Christophe
authors: C
authors: Glorieux
authors: Mélanie
authors: M
authors: Creton
authors: Edouard
authors: E
authors: Delaive
authors: Marc
authors: M
authors: Dieu
authors: Martine
authors: M
authors: Raes
authors: Philippe
authors: P
authors: Levêque
authors: Bernard
authors: B
authors: Gallez
authors: Matthieu
authors: M
authors: Depuydt
authors: Jean-François
authors: JF
authors: Collet
authors: Pedro Buc
authors: PB
authors: Calderon
authors: Julien
authors: J
authors: Verrax
mesh_terms: D020816:Amino Acid Motifs; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D020014:K562 Cells; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D059748:Proteolysis; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; C493165:HSP90AB1 protein, human; D017382:Reactive Oxygen Species; D007501:Iron