Atomic cryoEM structure of Hsp90-Hsp70-Hop-GR

Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity which is essential for its chaperone activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation.

Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function ^[1–6]. Engages with a range of client protein classes via its interaction with various co-chaperone proteins or complexes, that act as adapters, simultaneously able to interact with the specific client and the central chaperone itself ^[6]. Recruitment of ATP and co-chaperone followed by client protein forms a functional chaperone.

After the completion of the chaperoning process, properly folded client protein and co-chaperone leave HSP90 in an ADP-bound partially open conformation and finally, ADP is released from HSP90 which acquires an open conformation for the next cycle ^{[7, 8]}. Plays a critical role in mitochondrial import, delivers preproteins to the mitochondrial import receptor TOMM70 ^[2]. 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 three different levels ^[9]. In the first place, they alter the steady-state levels of certain transcription factors in response to various physiological cues ^[9]. Second, they modulate the activity of certain epigenetic modifiers, such as histone deacetylases or DNA methyl transferases, and thereby respond to the change in the environment ^[9].

Third, they participate in the eviction of histones from the promoter region of certain genes and thereby turn on gene expression ^[9]. Binds bacterial lipopolysaccharide (LPS) and mediates LPS-induced inflammatory response, including TNF secretion by monocytes ^[10]. Antagonizes STUB1-mediated inhibition of TGF-beta signaling via inhibition of STUB1-mediated SMAD3 ubiquitination and degradation ^[11].

Mediates the association of TOMM70 with IRF3 or TBK1 in mitochondrial outer membrane which promotes host antiviral response ^{[12, 13]} (Microbial infection) Seems to interfere with N.meningitidis NadA-mediated invasion of human cells. Decreasing HSP90 levels increases adhesion and entry of E.coli expressing NadA into human Chang cells; increasing its levels leads to decreased adhesion and invasion

Receptor for glucocorticoids (GC) ^{[1, 2]}. Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors ^[3]. Affects inflammatory responses, cellular proliferation and differentiation in target tissues.

Involved in chromatin remodeling ^[4]. Plays a role in rapid mRNA degradation by binding to the 5' UTR of target mRNAs and interacting with PNRC2 in a ligand-dependent manner which recruits the RNA helicase UPF1 and the mRNA-decapping enzyme DCP1A, leading to RNA decay ^[5]. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth (By similarity) Has transcriptional activation and repression activity ^[6–14].

Mediates glucocorticoid-induced apoptosis ^[15]. Promotes accurate chromosome segregation during mitosis ^[16]. May act as a tumor suppressor ^[16].

May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic gene expression (By similarity) Acts as a dominant negative inhibitor of isoform Alpha ^{[12, 17, 18]}. Has intrinsic transcriptional activity independent of isoform Alpha when both isoforms are coexpressed ^{[11, 19]}. Loses this transcription modulator function on its own ^[12].

Has no hormone-binding activity ^[18]. May play a role in controlling glucose metabolism by maintaining insulin sensitivity (By similarity). Reduces hepatic gluconeogenesis through down-regulation of PEPCK in an isoform Alpha-dependent manner ^[19].

Directly regulates STAT1 expression in isoform Alpha-independent manner ^[19] Has lower transcriptional activation activity than isoform Alpha. Exerts a dominant negative effect on isoform Alpha trans-repression mechanism ^[12] Increases activity of isoform Alpha More effective than isoform Alpha in transcriptional activation, but not repression activity Has transcriptional activation activity Has transcriptional activation activity Has transcriptional activation activity Has highest transcriptional activation activity of all isoforms created by alternative initiation ^{[8, 14]}. Has transcriptional repression activity ^[15].

Mediates glucocorticoid-induced apoptosis ^{[15, 14]} Has transcriptional activation activity Has transcriptional activation activity Has lowest transcriptional activation activity of all isoforms created by alternative initiation ^{[8, 14]}. Has transcriptional repression activity ^[15]