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The heat shock protein (Hsp) sequences, because of their ubiquity and high degree of conservation, provide useful models for phylogenetic analysis. In this paper I have carried out a global alignment of all available sequences (a total of 31) for the 90-kD heat shock protein (Hsp90) family. The minimum amino acid identity that is seen between presently known Hsp90 homologs is about 40% over the entire length, indicating that it is a highly conserved protein. Based on the alignment, a number of signature sequences that either are distinctive of the Hsp90 family or that distinguish between the cytosolic and the endoplasmic reticular forms of Hsp90 have been identified. Detailed phylogenetic analyses based on Hsp90 sequences reported here strongly indicate that the cytosolic and the endoplasmic reticulum (ER) resident forms of Hsp90 constitute paralogous gene families which arose by a gene duplication event that took place very early in the evolution of eukaryotic cells. A minimum of two additional gene duplication events, which took place at a later time, are required to explain the presence of two different forms of Hsp90 that are found in fungi and vertebrate species. In a consensus neighbor-joining bootstrap tree based on Hsp90 sequences, plants and animals species grouped together 989 times of 1,000 (a highly significant score), indicating a closer relationship between them as compared to fungi. A closer affiliation of plant and animal species was also observed in the maximum-parsimony tree, although the relationship was not significantly supported by this method. A survey of the recent literature on this subject indicates that depending on the protein sequence and the methods of phylogenetic analysis, the animal species are indicated as closer relatives to either plants or fungi with significant statistical support for both topologies. Thus the relationship among the animal, plant, and fungi kingdoms remains an unresolved issue at the present time.
Mol Biol Evol 1995 Nov
PMID:Phylogenetic analysis of the 90 kD heat shock family of protein sequences and an examination of the relationship among animals, plants, and fungi species. 852 40

The ubiquitous heat shock protein Hsp90 appears to participate directly in the function of a broad range of cellular signal transduction components, including steroid hormone receptors; however, an evolutionarily related subclass of intracellular receptors, exemplified by the retinoid receptors RAR and RXR, had been inferred from biochemical studies to function independently of Hsp90. To examine this issue genetically, we measured mammalian and avian retinoid receptor activity in a Saccharomyces cerevisiae strain in which the expression of the yeast Hsp90 homologue could be conditionally repressed approximately 20-fold relative to wild type. We tested transcriptional activation by RAR or RXR-RAR, from two types of retinoic acid response elements, triggered by three different agonist ligands. In every condition, we found that activation was severely compromised under conditions of low Hsp90 expression. We showed that the defect was in signal transduction rather than transcription activation per se, and that high affinity hormone binding was abolished in extracts of cells producing low levels of Hsp90. We suggest that Hsp90 may function in at least one step of signal transduction by all members of the intracellular receptor superfamily.
Mol Biol Cell 1995 Dec
PMID:A role for Hsp90 in retinoid receptor signal transduction. 859 Aug 9

Although Rafs play a central role in signal transduction, the mechanism(s) by which they become activated is poorly understood. Raf-1 activation is dependent on the protein's ability to bind Ras, but Ras binding is insufficient to activate Raf-1 tyrosine phosphorylation to this Ras-induced activation, in the absence of an over-expressed tyrosine kinase. We demonstrate that Raf-1 purified form Sf9 cells coinfected with baculovirus Ras but not Src could be inactivated by protein tyrosine phosphatase PTP-1B. 14-3-3 and Hsp90 proteins blocked both the tyrosine dephosphorylation and inactivation of Raf-1, suggesting that Raf-1 activity is phosphotyrosine dependent. In Ras-transformed NIH 3T3 cells, a minority of Raf-1 protein was membrane associated, but essentially all Raf-1 activity and Raf-1 phosphotyrosine fractionated with plasma membranes. Thus, the tyrosine-phosphorylated and active pool of Raf-1 constitute a membrane-localized subfraction which could also be inactivated with PTP-1B. By contrast, B-Raf has aspartic acid residues at positions homologous to those of the phosphorylated tyrosines (at 340 and 341) of Raf-1 and displays a high basal level of activity. B-Raf was not detectably tyrosine phosphorylated, membrane localized, or further activated upon Ras transformation, even though B-Raf has been shown to bind to Ras in vitro. We conclude that tyrosine phosphorylation is an essential component of the mechanism by which Ras activates Raf-1 kinase activity and that steady-state activated Ras is insufficient to activate B-Raf in vivo.
Mol Cell Biol 1996 Mar
PMID:Ras-induced activation of Raf-1 is dependent on tyrosine phosphorylation. 862 47

Molecular chaperones have been implicated in the formation of active p60v-src tyrosine kinase. In Saccharomyces cerevisiae, expression of p60v-src causes cell death, a phenomenon that requires functional Hsp90. We show here that mutations in a member of a second class of chaperones, the yeast dnaJ homologue YDJ1, suppress the lethality caused by p60v-src. One p60v-src-resistant ydj1 mutant, ydj1-39, which has two point mutations in the highly conserved "J" domain, has reduced levels of v-src mRNA and protein. However, a ydj1 null mutant produces normal quantities of active p60v-src, indicating that Ydj1p facilitates, but is not essential for, the formation of active p60v-src. We also report p60v-src-resistance in a previously identified temperature-sensitive ydj1 mutant, ydj1-151. In this mutant, the level of p60v-src remains unaltered, but the protein is much less active in vivo. In addition, p60v-src immunoprecipitates from the ydj1-151 strain contained Hsp90 and Hsp70 in greater amounts than in wild-type strains. Ydj1 protein was also detected in p60v-src immunoprecipitates from both wild-type and ydj1-151 strains. These results indicate that Ydj1p participates in the formation of active p60v-src via molecular chaperone complexes.
Mol Biol Cell 1996 Jan
PMID:The Ydj1 molecular chaperone facilitates formation of active p60v-src in yeast. 874 42

Mutations in genes encoding the molecular chaperones Hsp90 and Ydj1p suppress the toxicity of the protein tyrosine kinase p60v-src in yeast by reducing its levels or its kinase activity. We describe isolation and characterization of novel p60v-src-resistant, temperature-sensitive cdc37 mutants, cdc37-34 and cdc37-17, which produce less p60v-src than the parental wild-type strain at 23 degrees C. However, p60v-src levels are not low enough to account for the resistance of these strains. Asynchronously growing cdc37-34 and cdc37-17 mutants arrest in G1 and G2/M when shifted from permissive temperatures (23 degrees C) to the restrictive temperature (37 degrees C), but hydroxyurea-synchronized cdc37-34 and cdc37-17 mutants arrest in G2/M when released from the hydroxyurea block and shifted from 23 to 37 degrees C. The previously described temperature-sensitive cdc37-1 mutant is p60v-src-sensitive and produces wild-type amounts of p60v-src at permissive temperatures but becomes p60v-src-resistant at its restrictive temperature, 38 degrees C. In all three cdc37 mutants, inactivation of Cdc37p by incubation at 38 degrees C reduces p60v-src-dependent tyrosine phosphorylation of yeast proteins to low or undetectable levels. Also, p60v-src levels are enriched in urea-solubilized extracts and depleted in detergent-solubilized extracts of all three cdc37 mutants prepared from cells incubated at the restrictive temperature. These results suggest that Cdc37p is required for maintenance of p60v-src in a soluble, biologically active form.
Mol Biol Cell 1996 Sep
PMID:CDC37 is required for p60v-src activity in yeast. 888 35

Hsp90 interacts with Sti1 (p60) in lysates of yeast and vertebrate cells. Here we provide the first analysis of their interaction in vivo. Saccharomyces cerevisiae mutations that eliminate Sti1 or reduce intracellular concentrations of Hsp90 individually have little or no effect on growth at normal temperatures. However, when combined, the mutations greatly reduce or eliminate growth. Furthermore, overexpression of Sti1 has allele-specific effects on cells carrying various hsp90ts point mutations. These genetic interactions provide strong evidence that Hsp90 and Sti1 interact in vivo and that their functions are closely allied. Indeed, deletion of STI1 reduces the in vivo activity of the Hsp90 target protein, glucocorticoid receptor (GR). Mutations in GR that eliminate interaction with Hsp90 also eliminate the effects of the sti1 deletion. Examination of GR protein complexes in the sti1 deletion mutant reveals a selective increase in the concentration of GR-Ydj1 complexes, supporting previous hypotheses that Ydj1 functions at an early step in the maturation of GR and that Sti1 acts at an intermediate step. Deletion of STI1 also reduces the in vivo activity of another, unrelated Hsp90 target protein, v-Src. Our data indicate that Sti1 is a general factor in the maturation of Hsp90 target proteins and support earlier suggestions that Hsp90 matures even very different target proteins by a similar mechanism.
Mol Cell Biol 1997 Jan
PMID:In vivo analysis of the Hsp90 cochaperone Sti1 (p60). 897 12

A cDNA for human FKBP51 has been cloned and sequenced, and protein products have been expressed in both in vitro and bacterial systems. The deduced amino acid sequence for human FKBP51 is 90% identical to sequences of recently described murine proteins and is 55% identical to the sequence of human FKBP52. Human FKBP51 mRNA is expressed in a wide range of tissues, and the protein has peptidylprolyl isomerase activity that is inhibited by FK506 but not cyclosporine. FKBP51 is the same as a previously described progesterone receptor-associated immunophilin that, similar to FKBP52 and cyclophilin 40, is an Hsp90-binding protein and appears in functionally mature steroid receptor complexes along with Hsp90 and p23. Each of the three receptor-associated immunophilins displays interactions with progesterone receptor that are more dynamic than Hsp90-receptor interactions. Whereas FKBP52 and FKBP51 compete about equally well for binding to Hsp90 in a purified system, FKBP51 accumulates preferentially in progesterone receptor complexes assembled in a cell-free system. This observation provides a precedent for differential interactions between Hsp90-associated immunophilins and target proteins such as steroid receptors.
Mol Cell Biol 1997 Feb
PMID:Molecular cloning of human FKBP51 and comparisons of immunophilin interactions with Hsp90 and progesterone receptor. 900 Dec 12

The heat shock response of a fish which inhabits a highly stressful environment (Poeciliopsis lucida, a minnow from river systems of the Sonoran desert in northwestern Mexico) was investigated. Cells derived from this fish exhibited a typical heat shock response when exposed to elevated temperature, synthesizing high levels of 90 kDa, 70 kDa, and 30 kDa heat shock proteins (Hsp90, Hsp70, and Hsp30), as well as lower amounts of other heat shock proteins. Additional small heat shock proteins (sHSPs), including Hsp27, were induced after a prolonged heat shock at a time when synthesis of Hsp70 and Hsp30 was decreasing. Characterization of cDNA clones for hsp27 and hsp30 revealed that both are members of the alpha-crystallin/sHSP superfamily but belong to separate lineages within this gene family. The multiple isoforms of P. lucida Hsp30 appear to be members of a multigene family and are most closely related to salmon and Xenopus Hsp30s. In contrast, Hsp27 is highly similar to mammalian and avian sHSPs; it was synthesized as three isoforms which represented differentially phosphorylated forms of a single polypeptide. In Poeciliopsis, the various sHSPs may each perform a subset of the roles attributed to mammalian sHSPs. The conservation of phosphorylation sites in Hsp27 may indicate an involvement in signal transduction to the actin cytoskeleton. The hsp30 genes appear to have diverged more rapidly than the corresponding hsp27 genes; the various members of the Hsp30 family may function as molecular chaperones and, in this role, may be less evolutionarily constrained. Finally, the presence of these two classes of sHSP in a single taxon indicates that these two lineages arose by gene duplication early in the evolution of vertebrates and raises questions about the fate of homologs of Hsp30 in mammals and of Hsp27 in Xenopus.
Mol Biol Evol 1997 Oct
PMID:Low-molecular-weight heat shock proteins in a desert fish (Poeciliopsis lucida): homologs of human Hsp27 and Xenopus Hsp30. 933 45

The cellular response to environmental signals is largely dependent upon the induction of responsive protein kinase signaling pathways. Within these pathways, distinct protein-protein interactions play a role in determining the specificity of the response through regulation of kinase function. The interferon-induced serine/threonine protein kinase, PKR, is activated in response to various environmental stimuli. Like many protein kinases, PKR is regulated through direct interactions with activator and inhibitory molecules, including P58IPK, a cellular PKR inhibitor. P58IPK functions to represses PKR-mediated phosphorylation of the eukaryotic initiation factor 2alpha subunit (eIF-2alpha) through a direct interaction, thereby relieving the PKR-imposed block on mRNA translation and cell growth. To further define the molecular mechanism underlying regulation of PKR, we have utilized an interaction cloning strategy to identify a novel cDNA encoding a P58IPK-interacting protein. This protein, designated P52rIPK, possesses limited homology to the charged domain of Hsp90 and is expressed in a wide range of cell lines. P52rIPK and P58IPK interacted in a yeast two-hybrid assay and were recovered as a complex from mammalian cell extracts. When coexpressed with PKR in yeast, P58IPK repressed PKR-mediated eIF-2alpha phosphorylation, inhibiting the normally toxic and growth-suppressive effects associated with PKR function. Conversely, introduction of P52rIPK into these strains resulted in restoration of both PKR activity and eIF-2alpha phosphorylation, concomitant with growth suppression due to inhibition of P58IPK function. Furthermore, P52rIPK inhibited P58IPK function in a reconstituted in vitro PKR-regulatory assay. Our results demonstrate that P58IPK is inhibited through a direct interaction with P52rIPK which, in turn, results in upregulation of PKR activity. Taken together, our data describe a novel protein kinase-regulatory system which encompasses an intersection of interferon-, stress-, and growth-regulatory pathways.
Mol Cell Biol 1998 Feb
PMID:Regulation of interferon-induced protein kinase PKR: modulation of P58IPK inhibitory function by a novel protein, P52rIPK. 944 82

Steroid receptor complexes are assembled through an ordered, multistep pathway involving multiple components of the cytoplasmic chaperone machinery. Two of these components are Hsp70-binding proteins, Hip and Hop, that have some limited homology in their C-terminal regions, outside the sequences mapped for Hsp70 binding. Within this region of Hip is a DPEV sequence that occurs twice; in Hop, one DPEV sequence plus a partial second sequence occurs. In an effort to better understand Hip function as it relates to assembly of progesterone receptor complexes, the DPEV region of Hip was targeted for mutations. Each DPEV sequence was mutated to an APAV sequence, singly or in combination. The combined mutation, APAV2, was further combined with a deletion of Hip's tetratricopeptide repeat region that is required for Hsp70 binding or with a deletion of Hip's GGMP repeat. An additional mutant was prepared by truncation of Hip's DPEV-containing C terminus. By comparing interactions of various Hip forms with Hsp70, it was determined that mutation of the DPEV sequences created a dominant inhibitory form of Hip. The mutant Hip-Hsp70 complex was not prevented from interacting with progesterone receptor, but the mutant caused a dose-dependent inhibition of receptor assembly with Hsp90. The behavior of the Hip mutant is consistent with a model in which Hip and Hop are required to facilitate the transition from an early receptor complex with Hsp70 into later complexes containing Hsp90.
Mol Cell Biol 1998 Feb
PMID:Mutation of Hip's carboxy-terminal region inhibits a transitional stage of progesterone receptor assembly. 944 91


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