Chaperoning of glucocorticoid receptors.
A multiprotein hsp90/hsp70-based chaperone machinery functions as a 'cradle-to-grave' system for regulating the steroid binding, trafficking and turnover of the glucocorticoid receptor (GR). In an ATP-dependent process where hsp70 and hsp90 act as essential chaperones and Hop, hsp40, and p23 act as nonessential co-chaperones, the machinery assembles complexes between the ligand binding domain of the GR and hsp90. During GR-hsp90 heterocomplex assembly, the hydrophobic ligand-binding cleft is opened to access by steroid, and subsequent binding of steroid within the cleft triggers a transformation of the receptor such that it engages in more dynamic cycles of assembly/disassembly with hsp90 that are required for rapid dynein-dependent translocation to the nucleus. Within the nucleus, the hsp90 chaperone machinery plays a critical role both in GR movement to transcription regulatory sites and in the disassembly of regulatory complexes as the hormone level declines. The chaperone machinery also plays a critical role in stabilization of the GR to ubiquitylation and proteasomal degradation. The initial GR interaction with hsp70 appears to be critical for the triage between hsp90 heterocomplex assembly and preservation of receptor function vs CHIP-dependent ubiquitylation and proteasomal degradation. The hsp90 chaperone machinery is ubiquitous and functionally conserved among eukaryotes, and it is possible that all physiologically significant actions of hsp90 require the hsp70-dependent assembly of client protein-hsp90 heterocomplexes.
Pratt
W B
WB
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Morishima
Y
Y
Murphy
M
M
Harrell
M
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008024:Ligands; D018832:Molecular Chaperones / Q000502:physiology*; D021381:Protein Transport; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000502:physiology*
D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D018832:Molecular Chaperones; D011965:Receptors, Glucocorticoid