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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of key regulators controlling homeostasis and cell fate are chaperoned by the Hsp90 folding machine. In this issue of Molecular Cell, report the discovery of a new stress-regulated cochaperone, Aha1, which accelerates the dynamics of this machine.
Mol Cell 2002 Dec
PMID:Aha, another regulator for hsp90 chaperones. 1250 7

Client protein activation by Hsp90 involves a plethora of cochaperones whose roles are poorly defined. A ubiquitous family of stress-regulated proteins have been identified (Aha1, activator of Hsp90 ATPase) that bind directly to Hsp90 and are required for the in vivo Hsp90-dependent activation of clients such as v-Src, implicating them as cochaperones of the Hsp90 system. In vitro, Aha1 and its shorter homolog, Hch1, stimulate the inherent ATPase activity of yeast and human Hsp90. The identification of these Hsp90 cochaperone activators adds to the complex roles of cochaperones in regulating the ATPase-coupled conformational changes of the Hsp90 chaperone cycle.
Mol Cell 2002 Dec
PMID:Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. 1250 97

Cytosolic chaperones stabilize cellular proteins under stress conditions and protect nascent protein chains during normal growth. Recent data from Young et al. (2003) extend the function of chaperones by demonstrating that Hsp90 and Hsp70 specifically interact with the mitochondrial protein import receptor Tom70 at the outer membrane and are required for translocation of precursor proteins.
Mol Cell 2003 Jan
PMID:A new connection: chaperones meet a mitochondrial receptor. 1253 12

Geldanamycin (GA) is an antibiotic produced by Actinomyces, which specifically inhibits the function of the heat shock protein 90 family. Treatment of a murine macrophage cell line (J774) with GA resulted in a reduced response to Escherichia coli lipopolysaccharide (LPS) as visualized by a decrease of NF-kappaB translocation into the nucleus and secretion of tumor necrosis factor alpha (TNF-alpha). To elucidate the mechanism of this effect, the expression of CD14, the formal LPS receptor, was analyzed. Cells treated with GA showed a reduced level of surface CD14 detected by immunostaining, whereas the expression of other surface receptors, such as FC-gamma receptor and tumor necrosis factor receptors (TNF-R1 and TNF-R2), was unaffected. The reduced surface level of CD14 was not due to a reduction in its expression because CD14 steady state mRNA levels or the total cellular pool of CD14 was not altered by GA treatment. Surface CD14 was more rapidly internalized after GA treatment (2-3 h) than after incubation with cycloheximide. Immunostaining of permeabilized cells after GA treatment revealed a higher intracellular content of CD14 colocalizing with calnexin, an endoplasmic reticulum (ER) protein. These results suggest that the decrease in CD14 surface expression after GA treatment is due to rapid internalization without new replacement. These effects may be due to the inhibition of Hsp90 and Grp94 by GA in macrophages.
Mol Biol Cell 2003 Feb
PMID:Geldanamycin treatment ameliorates the response to LPS in murine macrophages by decreasing CD14 surface expression. 1258 68

Activation of client proteins by the Hsp90 molecular chaperone is dependent on binding and hydrolysis of ATP, which drives a molecular clamp via transient dimerization of the N-terminal domains. The crystal structure of the middle segment of yeast Hsp90 reveals considerable evolutionary divergence from the equivalent regions of other GHKL protein family members such as MutL and GyrB, including an additional domain of new fold. Using the known structure of the N-terminal nucleotide binding domain, a model for the Hsp90 dimer has been constructed. From this structure, residues implicated in the ATPase-coupled conformational cycle and in interactions with client proteins and the activating cochaperone Aha1 have been identified, and their roles functionally characterized in vitro and in vivo.
Mol Cell 2003 Mar
PMID:Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions. 1266 48

CpG motifs originating from bacterial DNA (CpG DNA) can act as danger signals for the mammalian immune system. These CpG DNA motifs like many other pathogen-associated molecular patterns are believed to be recognized by a member of the toll-like receptor family, TLR-9. Here we show results suggesting that heat shock protein 90 (hsp90) is also implicated in the recognition of CpG DNA. Hsp90 was characterized as a binder to oligodeoxynucleotides (ODNs) containing CpG motifs (CpG ODNs) after several purification steps from crude protein extracts of peripheral blood mononuclear cells. This finding was further supported by direct binding of CpG ODNs to commercially available human hsp90. Additionally, immunohistochemistry studies showed redistribution of hsp90 upon CpG ODN uptake. Thus, we propose that hsp90 can act as a ligand transfer molecule and/or play a central role in the signaling cascade induced by CpG DNA.
Cell Mol Life Sci 2003 Feb
PMID:Hsp90 binds CpG oligonucleotides directly: implications for hsp90 as a missing link in CpG signaling and recognition. 1267 5

The competence of the glucocorticoid receptor to regulate gene expression is thought to depend on Hsp70-driven continuous reactivation following spontaneous inactivation of its hormone-binding state. We show here that the glucocorticoid-binding capacity of HeLa cells fell with increasing temperature in the range 43-45 degrees C in a manner that closely paralleled the loss of soluble receptor protein. Receptor activity was maintained during moderate (43 degrees C) but not severe (45 degrees C) heat shock. Hsp70 was rapidly rendered insoluble and was replenished by soluble chaperone at 43 but not 45 degrees C. In heat-conditioned cells expressing different levels of Hsp70, we observed a positive correlation between the concentration of active receptor and the amount of Hsp70 rendered insoluble by heat shock. Much higher amounts of Hsp70 were rendered insoluble and receptor competence to regulate gene expression was preserved after severe heat shock of appropriately heat-conditioned cells. An excess of Hsp90 was found associated with resolubilized heat-inactivated receptor from severely heat-shocked cells. The data indicate that GR activity is maintained, provided that denaturation and/or aggregation of the receptor is prevented by Hsp70; and that the concentration of the chaperone is the limiting determinant of receptor activity in heat-shocked HeLa cells.
Mol Cell Endocrinol 2003 Mar 28
PMID:Maintenance of glucocorticoid receptor function following severe heat-shock of heat-conditioned cells. 1270 98

CHIP is a cochaperone of Hsp70 that inhibits Hsp70-dependent refolding in vitro. However, the effect of altered expression of CHIP on the fate of unfolded proteins in mammalian cells has not been determined. Surprisingly, we found that overexpression of CHIP in fibroblasts increased the refolding of proteins after thermal denaturation. This effect was insensitive to geldanamycin, an Hsp90 inhibitor, and required the tetratricopeptide repeat motifs but not the U-box domain of CHIP. Inhibition of Hsp70 chaperone activity abolished the effects of CHIP on protein folding, indicating that the CHIP-mediated events were Hsp70 dependent. Hsp40 competitively inhibited the CHIP-dependent refolding, which is consistent with in vitro data indicating that these cofactors act on Hsp70 in the ATP-bound state and have opposing effects on Hsp70 ATPase activity. Consistent with these observations, CHIP overexpression did not alter protein folding in the setting of ATP depletion, when Hsp70 is in the ADP-bound state. Concomitant with its effects on refolding heat-denatured substrates, CHIP increased the fraction of nascent chains coimmunoprecipitating with Hsc70, but only when sufficient ATP was present to allow Hsp70 to cycle rapidly. Our data suggest that, consistent with in vitro studies, CHIP attenuates the Hsp70 cycle in living cells. The impact of this effect on the fate of unfolded proteins in cells, however, is different from what might be expected from the in vitro data. Rather than resulting in inhibited refolding, CHIP increases the folding capacity of Hsp70 in eukaryotic cells.
Mol Cell Biol 2003 Jul
PMID:Overexpression of the cochaperone CHIP enhances Hsp70-dependent folding activity in mammalian cells. 1283 80

Eukaryotic cells utilize multiple mitogen-activated protein kinases (MAPKs) to transmit various extracellular stimuli to the nucleus. A subfamily of MAPKs that mediates environmental stress stimuli is also called stress-activated protein kinase (SAPK), which has crucial roles in cellular survival under stress conditions as well as inflammatory responses. Here we report that Cdc37, an evolutionarily conserved kinase-specific chaperone, is a positive regulator of Spc1 SAPK in the fission yeast Schizosaccharomyces pombe. Through a genetic screen, we have identified cdc37 as a mutation that compromises signaling through Spc1 SAPK. The Cdc37 protein physically interacts with Spc1, and the cdc37 mutation affects both the cellular level of the Spc1 protein and stress-induced Spc1 phosphorylation by Wis1 MAPK kinase (MAPKK). Consistently, expression of the stress response genes regulated by the Spc1 pathway is compromised in cdc37 mutant cells. On the other hand, a mutation in Hsp90, which often cooperates with Cdc37 in chaperoning protein kinases, does not affect Spc1 SAPK. These results suggest that Spc1 SAPK is a novel client protein for the Cdc37 chaperone, and the Cdc37 function is important to maintain the stability of the Spc1 protein and to facilitate stress signaling from Wis1 MAPKK to Spc1 SAPK.
Mol Cell Biol 2003 Aug
PMID:Identification of Cdc37 as a novel regulator of the stress-responsive mitogen-activated protein kinase. 1286 Oct 1

Heme-responsive motifs (HRMs) mediate heme regulation of diverse regulatory proteins. The heme activator protein Hap1 contains seven HRMs, but only one of them, HRM7, is essential for heme activation of Hap1. To better understand the molecular basis underlying the biological significance of HRMs, we examined the effects of various mutations of HRM7 on Hap1. We found that diverse mutations of HRM7 significantly diminished the extent of Hap1 activation by heme and moderately enhanced the interaction of Hap1 with Hsp90. Furthermore, deletions of nonregulatory sequences completely abolished heme activation of Hap1 and greatly enhanced the interaction of Hap1 with Hsp90. These results show that the biological functions of HRMs and Hsp90 are highly sensitive to structural changes. The unique role of HRM7 in heme activation stems from its specific structural environment, not its mere presence. Likewise, the role of Hsp90 in Hap1 activation is dictated by the conformational or structural state of Hap1, not by the mere strength of Hap1-Hsp90 interaction. It appears likely that HRM7 and Hsp90 act together to promote the Hap1 conformational changes that are necessary for Hap1 activation. Such fundamental mechanisms of HRM-Hsp90 cooperation may operate in diverse regulatory systems to mediate signal transduction.
Mol Cell Biol 2003 Aug
PMID:Structural environment dictates the biological significance of heme-responsive motifs and the role of Hsp90 in the activation of the heme activator protein Hap1. 1289 55


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