8h77
Hsp90-AhR-p23-XAP2 complex
Structural highlights
FunctionHS90B_MOUSE 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 linked to its ATPase 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. 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. 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. 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. They first alter the steady-state levels of certain transcription 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 thereby respond to the change in the environment. Third, they participate in the eviction of histones from the promoter region of certain genes and thereby 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 thereby protecting from auto-ubiquitination and degradation by the proteasomal machinery. Main chaperone involved in the phosphorylation/activation of the STAT1 by chaperoning both JAK2 and PRKCE under heat shock and in turn, activates its own transcription. Involved in the translocation into ERGIC (endoplasmic reticulum-Golgi intermediate compartment) of leaderless cargos (lacking the secretion signal sequence) such as the interleukin 1/IL-1; the translocation process is mediated by the cargo receptor TMED10.[UniProtKB:P08238] Publication Abstract from PubMedAryl hydrocarbon receptor (AhR) is an important ligand-activated transcription factor involved in the regulation of various important physiological functions. Here, we report the cryo-EM structures of the Hsp90-AhR-p23 complex with or without bound XAP2, where the structure of the mouse AhR PAS-B domain is resolved. A highly conserved bridge motif of AhR is responsible for the interaction with the Hsp90 dimeric lumen. The ligand-free AhR PAS-B domain is attached to the Hsp90 dimer and is stabilized in the complex with bound XAP2. In addition, the DE-loop and a group of conserved pocket inner residues in the AhR PAS-B domain are found to be important for ligand binding. These results reveal the structural basis of the biological functions of AhR. Moreover, the protein purification method presented here allows the isolation of stable mouse AhR protein, which could be used to develop high-sensitivity biosensors for environmental pollutant detection. Cryo-EM structure of the cytosolic AhR complex.,Wen Z, Zhang Y, Zhang B, Hang Y, Xu L, Chen Y, Xie Q, Zhao Q, Zhang L, Li G, Zhao B, Sun F, Zhai Y, Zhu Y Structure. 2023 Mar 2;31(3):295-308.e4. doi: 10.1016/j.str.2022.12.013. Epub 2023 , Jan 16. PMID:36649707[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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