A Model of Protein Targeting Mediated by Immunophilins and Other Proteins That Bind to hsp90 via Tetratricopeptide Repeat Domains

Owens-Grillo, Janet K.; Czar, Michael J.; Hutchison, Kevin A.; Hoffmann, Kai; Perdew, Gary H.; Pratt, William B.

doi:10.1074/jbc.271.23.13468

Cited by 160 publications

(169 citation statements)

References 65 publications

(51 reference statements)

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“…Little is known about the potential functions of FKBP51, FKBP52, and CyP-40. Pratt and co-workers (38,39) have provided evidence that FKBP52 may be involved in the nuclear transport of steroid receptors. The immunophilins, having peptidyl-prolyl isomerase activity, could also interact with the receptor to modulate its conformational state either before or after the binding of hormone.…”

Section: Resultsmentioning

confidence: 99%

The Assembly of Progesterone Receptor-hsp90 Complexes Using Purified Proteins

Kosano¹,

Stensgard²,

Charlesworth³

et al. 1998

Journal of Biological Chemistry

231

250

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The progesterone receptor can be reconstituted into hsp90-containing complexes in vitro, and the resulting complexes are needed to maintain hormone binding activity. This process requires ATP/Mg 2؉ , K ؉ , and several axillary proteins. We have developed a defined system for the assembly of progesterone receptor complexes using purified proteins. Five proteins are needed to form complexes that are capable of maintaining hormone binding activity. These include hsp70 and its cochaperone, hsp40, the hsp70/hsp90-binding protein, Hop, hsp90, and the hsp90-binding protein, p23. The proteins Hip and FKBP52 were not required for this in vitro process even though they have been observed in receptor complexes. Each of the five proteins showed a characteristic concentration dependence. Similar concentrations of hsp70, hsp90, and p23 were needed for optimal assembly, but hsp40 and Hop were effective at about 1/10 the concentration of the other proteins, suggesting that these two proteins act catalytically or are needed at levels similar to the receptor concentration. ATP was required for the functioning of both hsp70 and hsp90. The binding of hsp70 to the receptor requires hsp40 and about 10 M ATP; however, hsp90 binding appears to occur subsequent to hsp70 binding and is optimal with 1 mM ATP. A three-step model is presented to describe the assembly process.When extracted from tissue cytosol, receptors for progesterone (PR), 1 glucocorticoid (GR), and other steroids exist in heteromeric complexes containing heat shock protein 90 (hsp90) and several additional proteins (1-3). Recent information on the assembly of these complexes has been gained mainly through the use of an in vitro system consisting of immuneisolated progesterone (4) or glucocorticoid (5) receptor incubated in rabbit reticulocyte lysate. The formation of receptor complexes in this system is dependent upon ATP hydrolysis, the ions Mg 2ϩ and K ϩ , and the participation of a number of proteins (6, 7). When assembled in vitro, the mature avian progesterone receptor complex closely resembles that obtained from oviduct cytosol and contains hsp90, any one of three immunophilins, and a 23-kDa phosphoprotein, p23. It also contains variable sub-stoichiometric amounts of hsp70. The immunophilins include the cyclosporin A-binding protein, CyP-40, and two FK506-binding proteins, FKBP51 and FKBP52. Antibody inhibitor studies or depletion and reconstitution experiments indicate that hsp70 (6, 8), Hop, an intermediate in complex assembly (9), and p23 (10, 11) are essential for the formation of hsp90 complexes, but the actual roles of these and other proteins are still unclear.An intermediate in PR complex formation has been identified that contains submaximal amounts of hsp90, substantially more hsp70 than in the mature complex, and two additional proteins, Hop (p60) and Hip (p48) (6, 12). This complex does not contain immunophilins or p23. Hop (hsp-organizing protein) is a 60-kDa stress-related protein that binds to both hsp70 and hsp90 (9, 13-15). Hip (hsp70-interacting ...

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Section: Resultsmentioning

confidence: 99%

The Assembly of Progesterone Receptor-hsp90 Complexes Using Purified Proteins

Kosano¹,

Stensgard²,

Charlesworth³

et al. 1998

Journal of Biological Chemistry

231

250

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“…The TPR-containing domain of FKBP52, Cyp40, and protein phosphatase pp5 mediate the binding of these proteins to HSP90 [14][15][16]. Only a specific subset of TPR-containing proteins, with closely related TPR motifs, can bind HSP90.…”

Section: Introductionmentioning

confidence: 99%

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Itoh

Ogura

Komatsuda

et al. 1999

Biochemical Journal

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The 90-kDa heat shock protein (HSP90) acts as a specific molecular chaperone in the folding and regulates a wide range of associated proteins such as steroid hormone receptors. It is known that HSP90 possesses two different chaperone sites, both in the N-and C-domains, and that the chaperone activity of HSP90 is blocked by binding of geldanamycin (GA) to the Ndomain, the same as the ATP-binding site. Here we show that Cisplatin [cis-diamminedichloroplatinum (II), CDDP], an antineoplastic agent, associates with HSP90 and reduces its chaperone activity. In order to analyse the binding proteins, bovine brain cytosols were applied to a CDDP-affinity column and binding proteins were eluted by CDDP. In the elutants, only 90-kDa protein bands were detected on SDS\PAGE, and the protein was cross-reacted with the anti-HSP90 antibody on immunoblotting. No protein bands were detected in the elutants

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“…hsp90 was proposed to be a mediator of protein trafficking over a decade ago (Pratt, 1992(Pratt, , 1993. Since then, ample evidence has accumulated indicating that hsp90 is required for the subcellular targeting of a variety of proteins, including the glucocorticoid receptor (Owens-Grillo et al, 1996;Czar et al, 1997;Silverstein et al, 1999;Galigniana et al, 2001), the dioxin receptor (Kazlauskas et al, 2001), the receptor tyrosine kinase ErbB2 (Xu et al, 2002), the epidermal growth factor receptor (Supino-Rosin et al, 2000), the CFTR (cystic fibrosis transmembrane regulator) chloride channel (Loo et al, 1998) and the G-protein G␣ 12 (Waheed and Jones, 2002). hsp90 is also required for protein translocation into mitochondria (Young et al, 2003) and peroxisomes (Crookes and Olsen, 1998).…”

Section: Introductionmentioning

confidence: 99%

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

Gerges¹,

Tran²,

Backos³

et al. 2004

J. Neurosci.

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The delivery of neurotransmitter receptors into synapses is essential for synaptic function and plasticity. In particular, AMPA-type glutamate receptors (AMPA receptors) reach excitatory synapses according to two distinct routes: a regulated pathway, which operates transiently during synaptic plasticity, and a constitutive pathway, which maintains synaptic function under conditions of basal transmission. However, the specific mechanisms that distinguish these two trafficking pathways are essentially unknown. Here, we evaluate the role of the molecular chaperone hsp90 (heat shock protein 90) in excitatory synaptic transmission in the hippocampus. On one hand, we found that hsp90 is necessary for the efficient neurotransmitter release at the presynaptic terminal. In addition, we identified hsp90 as a critical component of the cellular machinery that delivers AMPA receptors into the postsynaptic membrane. Using the hsp90-specific inhibitors radicicol and geldanamycin, we show that hsp90 is required for the constitutive trafficking of AMPA receptors into synapses during their continuous cycling between synaptic and nonsynaptic sites. In contrast, hsp90 function is not required for either the surface delivery of AMPA receptors into the nonsynaptic plasma membrane or for the acute, regulated delivery of AMPA receptors into synapses during plasticity induction (long-term potentiation). The synaptic cycling of AMPA receptors was also blocked by an hsp90-binding tetratricopeptide repeat (TPR) domain, suggesting that the role of hsp90 in AMPA receptor trafficking is mediated by a TPR domaincontaining protein. These results demonstrate new roles for hsp90 in synaptic function by controlling neurotransmitter release and, independently, by mediating the continuous cycling of synaptic AMPA receptors.

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A Model of Protein Targeting Mediated by Immunophilins and Other Proteins That Bind to hsp90 via Tetratricopeptide Repeat Domains

Cited by 160 publications

References 65 publications

The Assembly of Progesterone Receptor-hsp90 Complexes Using Purified Proteins

The Assembly of Progesterone Receptor-hsp90 Complexes Using Purified Proteins

A novel chaperone-activity-reducing mechanism of the 90-kDa molecular chaperone HSP90

Independent Functions of hsp90 in Neurotransmitter Release and in the Continuous Synaptic Cycling of AMPA Receptors

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