Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P50502 (Hip)
 7,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Like other nuclear receptors, steroid hormone receptors form large protein hetero-complexes in their inactive, ligand-friendly state. Several heat-shock proteins, immunophilins and others have been identified as members of these highly dynamic complexes. The interaction kinetics and dynamics of hsp90, hsp70, p60 (Hop), FKBP52, FKBP51, p48 (Hip) and p23 have been assessed by a biosensor approach measuring the complex formation in real time. A core chaperone complex has been reconstituted from p60, hsp90 and hsp70. p60 forms a molecular bridge between hsp90 and hsp70 with an affinity in the range of 10(5) M(-1). Dynamics of hsp90-p60 complex formation is modulated by ATP through changes in the co-operativity of interaction. At low protein concentrations ATP stabilizes the complex. Binding of p23 to hsp90 did not change the affinity of the hsp90-p60 complex and the stabilizing effect of ATP. Saturation of the p48-hsp70 interaction could not be achieved, suggesting multiple binding sites. A picture of the protein complex, including stoichiometric coefficients, co-operativity of interaction and equilibrium-binding constants, has been formed.
 ...
PMID:Quantitative assessment of complex formation of nuclear-receptor accessory proteins. 1064 22

We have isolated two human ubiquitin-like (UbL) proteins that bind to a short peptide within the ATPase domain of the Hsp70-like Stch protein. Chap1 is a duplicated homologue of the yeast Dsk2 gene that is required for transit through the G2/M phase of the cell cycle and expression of the human full-length cDNA restored viability and suppressed the G2/M arrest phenotype of dsk2Delta rad23Delta Saccharomyces cerevisiae mutants. Chap2 is a homologue for Xenopus scythe which is an essential component of reaper-induced apoptosis in egg extracts. While the N-terminal UbL domains were not essential for Stch binding, Chap1/Dsk2 contains a Sti1-like repeat sequence that is required for binding to Stch and is also conserved in the Hsp70 binding proteins, Hip and p60/Sti1/Hop. These findings extend the association between Hsp70 members and genes encoding UbL sequences and suggest a broader role for the Hsp70-like ATPase family in regulating cell cycle and cell death events.
 ...
PMID:A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch. 1067 67

Reticulocyte lysate contains a chaperone system that assembles glucocorticoid receptor (GR).hsp90 heterocomplexes. Using purified proteins, we have prepared a five-protein heterocomplex assembly system consisting of two proteins essential for heterocomplex assembly-hsp90 and hsp70-and three proteins that act as co-chaperones to enhance assembly-Hop, hsp40, p23 [Morishima, Y., Kanelakis, K. C., Silverstein, A. M., Dittmar, K. D., Estrada, L., and Pratt, W. B. (2000) J. Biol. Chem. 275, 6894-6900]. The hsp70 co-chaperone Hip has been recovered in receptor.hsp90 heterocomplexes at an intermediate stage of assembly in reticulocyte lysate, and Hip is also thought to be an intrinsic component of the assembly machinery. Here we show that immunodepletion of Hip from reticulocyte lysate or addition of high levels of Hip to the purified five-protein system does not affect GR.hsp90 heterocomplex assembly or the activation of steroid binding activity that occurs with assembly. Despite the fact that Hip does not affect assembly, it is recovered in GR.hsp90 heterocomplexes assembled by both systems. In the five-protein system, Hip prevents inhibition of assembly by the hsp70 co-chaperone BAG-1, and cotransfection of Hip with BAG-1 opposes BAG-1 reduction of steroid binding activity in COS cells. We conclude that Hip is not a component of the assembly machinery but that it could play a regulatory role in opposition to BAG-1.
 ...
PMID:hsp70 interacting protein Hip does not affect glucocorticoid receptor folding by the hsp90-based chaperone machinery except to oppose the effect of BAG-1. 1108 80

This article presents a brief review of stressors, their cellular and intracellular targets, stress proteins, molecular chaperones, and other anti-stress mechanisms. New data are reported on cochaperones and multicellular structures in archaea. The molecular chaperoning systems of bacteria and eukaryotes have been studied for many years and are relatively well known in terms of their components and mechanisms of action, although many details remain to be elucidated and almost certainly other components will be discovered in the future. By comparison, the molecular chaperoning system of archaea is still unexplored. Since archaea have some molecular genetic and physiologic features similar to those of bacteria and some resembling those of eukaryotes, extrapolation from what is known of organisms from these two phylogenetic domains to archaeal species is unwarranted. For example, the components of the molecular chaperone machine, Hsp70(DnaK), Hsp40(DnaJ), and GrpE, in the archaeal species that have it, are closely related to bacterial counterparts, whereas the archaeal chaperonins are like the eukaryotic equivalents. Furthermore, many archaeal species lack the chaperone machine, in contrast to bacteria and eukaryotes that have it without any known exception. A search for the cochaperones trigger factor, Hop, Hip, BAG-1, and NAC in archaeal genomes demonstrated no conserved equivalents, but two families of archaeal molecules were identified that might be related to NAC and Hop, respectively. Multicellular structures with a single species such as packet and lamina are formed by Methanosarcina species, among which the best studied is M. mazeii. Multispecies multicellular structures are formed by a variety of archaeal organisms, which are either flat (biofilm) or globular (granule) and constitute a functional association or consortium. Details of morphology, formation, and internal organization are described for representative examples of multicellular structures. These may be seen as the result of primitive histogenesis reflecting primeval mechanisms of differentiation-development that might have evolved driven by environmental stressors. Cells in these complex threedimensional arrangements are not only positioned so they can interact with each other for more efficient functioning as in a tissue or organ, but are also protected from stressors. Single cells lacking the protective shield of other cells packed together with intercellular connective material, which is typical of multicellular structures, are directly exposed to environmental stressors and, thus, are at a disadvantage from the evolutionary standpoint. It seems reasonable to argue that differentiation-development leading to histogenesis might have arisen in primeval times as a consequence of the harsh conditions that primitive life forms had to endure, and that the ability to form tissue-like structures was a primary characteristic that ensured positive selection.
 ...
PMID:The molecular chaperone system and other anti-stress mechanisms in archaea. 1117 52

The Hsp70-interacting protein Hip binds to the adenosine triphosphatase domain of Hsp70, stabilizing it in the adenosine 5'-diphosphate-ligated conformation and promoting binding of target polypeptides. In mammalian cells, Hip is a component of the cytoplasmic chaperone heterocomplex that regulates signal transduction via interaction with hormone receptors and protein kinases. Analysis of the complete genome sequence of the model flowering plant Arabidopsis thaliana revealed 2 genes encoding Hip orthologs. The deduced sequence of AtHip-1 consists of 441 amino acid residues and is 42% identical to human Hip. AtHip-1 contains the same functional domains characterized in mammalian Hip, including an N-terminal dimerization domain, an acidic domain, 3 tetratricopeptide repeats flanked by a highly charged region, a series of degenerate GGMP repeats, and a C-terminal region similar to the Sti1/Hop/p60 protein. The deduced amino acid sequence of AtHip-2 consists of 380 amino acid residues. AtHip-2 consists of a truncated Hip-like domain that is 46% identical to human Hip, followed by a C-terminal domain related to thioredoxin. AtHip-2 is 63% identical to another Hip-thioredoxin protein recently identified in Vitis labrusca (grape). The truncated Hip domain in AtHip-2 includes the amino terminus, the acidic domain, and tetratricopeptide repeats with flanking charged region. Analyses of expressed sequence tag databases indicate that both AtHip-1 and AtHip-2 are expressed in A thaliana and that orthologs of Hip are also expressed widely in other plants. The similarity between AtHip-1 and its mammalian orthologs is consistent with a similar role in plant cells. The sequence of AtHip-2 suggests the possibility of additional unique chaperone functions.
 ...
PMID:Orthologs in Arabidopsis thaliana of the Hsp70 interacting protein Hip. 1159 66

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the folding and assembly of a limited set of "client" proteins, many of which are involved in signal transduction pathways. In vivo, it is found in complex with additional proteins, including the chaperones Hsp70, Hsp40, Hip and Hop (Hsp-interacting and Hsp-organising proteins, respectively), as well as high molecular mass immunophilins, such as FKBP59, and the small acidic protein p23. The role of these proteins in Hsp90-mediated assembly processes is poorly understood. It is known that ATP binding and hydrolysis are essential for Hsp90 function in vivo and in vitro. Here we show, for the first time, that human Hsp90 has ATPase activity in vitro. The ATPase activity is characterised using a sensitive assay based on a chemically modified form of the phosphate-binding protein from Escherichia coli. Human Hsp90 is a very weak ATPase, its activity is significantly lower than that of the yeast homologue, and it has a half-life of ATP hydrolysis of eight minutes at 37 degrees C. Using a physiological substrate of Hsp90, the ligand-binding domain of the glucocorticoid receptor, we show that this "client" protein can stimulate the ATPase activity up to 200-fold. This effect is highly specific and unfolded or partially folded proteins, which are known to bind to Hsp90, do not affect the ATPase activity. In addition, the peroxisome proliferator-activated receptor, which is related in both sequence and structure to the glucocorticoid receptor but which does not bind Hsp90, has no observable effect on the ATPase activity. We establish the effect of the co-chaperones Hop, FKBP59 and p23 on the basal ATPase activity as well as the client protein-stimulated ATPase activity of human Hsp90. In contrast with the yeast system, human Hop has little effect on the basal rate of ATP hydrolysis but significantly inhibits the client-protein stimulated rate. Similarly, FKBP59 has little effect on the basal rate but stimulates the client-protein stimulated rate further. In contrast, p23 inhibits both the basal and stimulated rates of ATP hydrolysis. Our results show that the ATPase activity of human Hsp90 is highly regulated by both client protein and co-chaperone binding. We suggest that the rate of ATP hydrolysis is critical to the mode of action of Hsp90, consistent with results that have shown that both over and under-active ATPase mutants of yeast Hsp90 have impaired function in vivo. We suggest that the tight regulation of the ATPase activity of Hsp90 is important and allows the client protein to remain bound to Hsp90 for sufficient time for activation to occur.
 ...
PMID:Stimulation of the weak ATPase activity of human hsp90 by a client protein. 1181 47

Many agents of physical, chemical, or biological nature, have the potential for causing cell stress. These agents are called stressors and their effects on cells are due to protein denaturation. Cells, microbes, for instance, perform their physiological functions and survive stress only if they have their proteins in the necessary concentrations and shapes. To be functional a protein shape must conform to a specific three-dimensional arrangement, named the native configuration. When a stressor (e.g., temperature elevation or heat shock, decrease in pH, hypersalinity, heavy metals) hits a microbe, it causes proteins to lose their native configuration, which is to say that stressors cause protein denaturation. The cell mounts an anti-stress response: house-keeping genes are down-regulated and stress genes are activated. Among the latter are the genes that produce the Hsp70(DnaK), Hsp60, and small heat protein (sHsp) families of stress proteins. Hsp70(DnaK) is part of the molecular chaperone machine together with Hsp40(DnaJ) and GrpE, and Hsp60 is a component of the chaperonin complex. Both the chaperone machine and the chaperonins play a crucial role in assisting microbial proteins to reach their native, functional configuration and to regain it when it is partially lost due to stress. Proteins that are denatured beyond repair are degraded by proteases so they do not accumulate and become a burden to the cell. All Archaea studied to date possess chaperonins but only some methanogens have the chaperone machine. A recent genome survey indicates that Archaea do not harbor well conserved equivalents of the co-chaperones trigger factor, Hip, Hop, BAG-1, and NAC, although the data suggest that Archaea have proteins related to Hop and to the NAC alpha subunit whose functions remain to be elucidated. Other anti-stress means involve osmolytes, ion traffic, and formation of multicellular structures. All cellular anti-stress mechanisms depend on genes whose products are directly involved in counteracting the effects of stressors, or are regulators. The latter proteins monitor and modulate gene activity. Biomethanation depends on the concerted action of at least three groups of microbes, the methanogens being one of them. Their anti-stress mechanisms are briefly discussed in this Chapter from the standpoint of their role in biomethanation with emphasis on their potential for optimizing bioreactor performance. Bioreactors usually contain stressors that come with the influent, or are produced during the digestion process. If the stressors reach levels above those that can be dealt with by the anti-stress mechanisms of the microbes in the bioreactor, the microbes will die or at least cease to function. The bioreactor will malfunction and crash. Manipulation of genes involved in the anti-stress response, particularly those pertinent to the synthesis and regulation of the Hsp70(DnaK) and Hsp60 molecular machines, is a promising avenue for improving the capacity of microbes to withstand stress, and thus to continue biomethanation even when the bioreactor is loaded with harsh waste. The engineering of methanogenic consortia with stress-resistant microbes, made on demand for efficient bioprocessing of stressor-containing effluents and wastes, is a tangible possibility for the near future. This promising biotechnological development will soon become a reality due to the advances in the study of the stress response and anti-stress mechanisms at the molecular and genetic levels.
 ...
PMID:Molecular biology of stress genes in methanogens: potential for bioreactor technology. 1274 62

The function of Tic40 during chloroplast protein import was investigated. Tic40 is an inner envelope membrane protein with a large hydrophilic domain located in the stroma. Arabidopsis null mutants of the atTic40 gene were very pale green and grew slowly but were not seedling lethal. Isolated mutant chloroplasts imported precursor proteins at a lower rate than wild-type chloroplasts. Mutant chloroplasts were normal in allowing binding of precursor proteins. However, during subsequent translocation across the inner membrane, fewer precursors were translocated and more precursors were released from the mutant chloroplasts. Cross-linking experiments demonstrated that Tic40 was part of the translocon complex and functioned at the same stage of import as Tic110 and Hsp93, a member of the Hsp100 family of molecular chaperones. Tertiary structure prediction and immunological studies indicated that the C-terminal portion of Tic40 contains a TPR domain followed by a domain with sequence similarity to co-chaperones Sti1p/Hop and Hip. We propose that Tic40 functions as a co-chaperone in the stromal chaperone complex that facilitates protein translocation across the inner membrane.
 ...
PMID:Tic40, a membrane-anchored co-chaperone homolog in the chloroplast protein translocon. 1280 12

Functional steroid receptor complexes are assembled and maintained by an ordered pathway of interactions involving multiple components of the cellular chaperone machinery. Two of these components, Hop and Hip, serve as co-chaperones to the major heat shock proteins (Hsps), Hsp70 and Hsp90, and participate in intermediate stages of receptor assembly. In an effort to better understand the functions of Hop and Hip in the assembly process, we focused on a region of similarity located near the C-terminus of each co-chaperone. Contained within this region is a repeated sequence motif we have termed the DP repeat. Earlier mutagenesis studies implicated the DP repeat of either Hop or Hip in Hsp70 binding and in normal assembly of the co-chaperones with progesterone receptor (PR) complexes. We report here that the DP repeat lies within a protease-resistant domain that extends to or is near the C-terminus of both co-chaperones. Point mutations in the DP repeats render the C-terminal regions hypersensitive to proteolysis. In addition, a Hop DP mutant displays altered proteolytic digestion patterns, which suggest that the DP-repeat region influences the folding of other Hop domains. Although the respective DP regions of Hop and Hip share sequence and structural similarities, they are not functionally interchangeable. Moreover, a double-point mutation within the second DP-repeat unit of Hop that converts this to the sequence found in Hip disrupts Hop function; however, the corresponding mutation in Hip does not alter its function. We conclude that the DP repeats are important structural elements within a C-terminal domain, which is important for Hop and Hip function.
 ...
PMID:Comparison of the carboxy-terminal DP-repeat region in the co-chaperones Hop and Hip. 1462 98

Multiple molecular chaperones interact with steroid receptors to promote functional maturation and stability of receptor complexes. The heat shock protein (Hsp)70 cochaperone Hip has been identified in conjunction with Hsp70, Hsp90, and the Hsp70/Hsp90 cochaperone Hop/Sti1p in receptor complexes during an intermediate stage of receptor assembly, but a functional requirement for Hip in the receptor assembly process has not been established. Because the budding yeast Saccharomyces cerevisiae contains orthologs for most of the receptor-associated chaperones yet lacks an orthologous Hip gene, we exploited the well-established yeast model for steroid receptor function to ask whether Hip can alter steroid receptor function in vivo. Introducing human Hip into yeast enhances hormone-dependent activation of a reporter gene by glucocorticoid receptor (GR). Because Hip does not similarly enhance signaling by mineralocorticoid, progesterone, or estrogen receptors, a general effect on transcription can be excluded. Instead, Hip promotes functional maturation of GR without increasing steady-state levels of GR protein. Unexpectedly, Hip binding to Hsp70 is not critical for boosting GR responsiveness to hormone. In conclusion, Hip functions by a previously unrecognized mechanism to promote the efficiency of GR maturation in cells.
 ...
PMID:The heat shock protein 70 cochaperone hip enhances functional maturation of glucocorticoid receptor. 1507 Oct 92


<< Previous 1 2 3 4 5 Next >>