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• W2128975348 abstract "Endoplasmic reticulum (ER) stress-induced activation of ATF6, an ER membrane-bound transcription factor, requires a dissociation step from its inhibitory regulator, BiP. It has been generally postulated that dissociation of the BiP-ATF6 complex is a result of the competitive binding of misfolded proteins generated during ER stress. Here we present evidence against this model and for an active regulatory mechanism for dissociation of the complex. Contradictory to the competition model that is based on dynamic binding of BiP to ATF6, our data reveal relatively stable binding. First, the complex was easily isolated, in contrast to many chaperone complexes that require chemical cross-linking. Second, ATF6 bound at similar levels to wild-type BiP and a BiP mutant form that binds substrates stably because of a defect in its ATPase activity. Third, ER stress specifically induced the dissociation of BiP from ER stress transducers while the competition model would predict dissociation from any specific substrate. Fourth, the ATF6-BiP complex was resistant to ATP-induced dissociation in vitro when isolated without detergents, suggesting that cofactors stabilize the complex. In favor of an active dissociation model, one specific region within the ATF6 lumenal domain was identified as a specific ER stress-responsive sequence required for ER stress-triggered BiP release. Together, our results do not support a model in which competitive binding of misfolded proteins causes dissociation of the BiP-ATF6 complex in stressed cells. We propose that stable BiP binding is essential for ATF6 regulation and that ER stress dissociates BiP from ATF6 by actively restarting the BiP ATPase cycle." @default.
• W2128975348 created "2016-06-24" @default.
• W2128975348 creator A5000877747 @default.
• W2128975348 creator A5009271793 @default.
• W2128975348 creator A5020566486 @default.
• W2128975348 creator A5061532825 @default.
• W2128975348 date "2005-02-01" @default.
• W2128975348 modified "2023-10-18" @default.
• W2128975348 title "Stable Binding of ATF6 to BiP in the Endoplasmic Reticulum Stress Response" @default.
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• W2128975348 doi "https://doi.org/10.1128/mcb.25.3.921-932.2005" @default.
• W2128975348 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/543992" @default.
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