Molecular chaperone that promotes the maturation, structuralmaintenance and proper regulation of specific target proteins involvedfor instance in cell cycle control and signal transduction. Undergoes afunctional cycle linked to its ATPase activity. This cycle probablyinduces conformational changes in the client proteins, thereby causingtheir activation. Interacts dynamically with various co-chaperones thatmodulate its substrate recognition, ATPase cycle and chaperone function. Engages with a range of clientprotein classes via its interaction with various co-chaperone proteinsor complexes, that act as adapters, simultaneously able to interactwith the specific client and the central chaperone itself. Recruitmentof ATP and co-chaperone followed by client protein forms a functionalchaperone. After the completion of the chaperoning process, properlyfolded client protein and co-chaperone leave HSP90 in an ADP-boundpartially open conformation and finally, ADP is released from HSP90which acquires an open conformation for the next cycle. Apart from its chaperone activity, it also plays a role in the regulation of the transcription machinery. HSP90 and its co-chaperones modulate transcription at least at threedifferent levels. They first alter the steady-state levels of certaintranscription factors in response to various physiological cues. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and therebyrespond to the change in the environment. Third, they participate inthe eviction of histones from the promoter region of certain genes andthereby turn on gene expression. Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation. Promotes cell differentiation by chaperoning BIRC2 and therebyprotecting from auto-ubiquitination and degradation by the proteasomalmachinery. Main chaperone involved in thephosphorylation/activation of the STAT1 by chaperoning both JAK2 andPRKCE under heat shock and in turn, activates its own transcription. Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderlesscargos (lacking the secretion signal sequence) such as the interleukin1/IL-1; the translocation process is mediated by the cargo receptorTMED10. [1-4]

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