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Results for “Multiprotein Complexes”

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PubMed1995

Cell adhesion and signal transduction: the Armadillo connection.

The products of the Drosophila segment polarity gene armadillo and its vertebrate homologue beta-catenin are components of the signal transduction pathway for Wingless/Wnt-1; this signal regulates cell-fate choices in embryos of the fruit fly Drosophila and vertebrates. Armadillo/beta-catenin is also a component of cell-cell adherens junctions in epithelia. How can these two seemingly distinct roles be reconciled? Evidence suggests that Armadillo has distinct functions: one in the adherens junction and one or more in the cytoplasm. The biochemical role of Armadillo may be to serve as a scaffold upon which different multiprotein complexes are assembled.

Journal Article↗

PubMed2000

Association of STATs with relatives and friends.

Members of the STAT family of transcription factors are present in species as diverse as mammals, insects and slime molds. Discovered as mediators of interferon-induced signals, the STATs were later shown to drive many different ligand-induced responses through receptor-induced tyrosine phosphorylation and dimerization. STAT1 also functions as a transcription factor, essential for the efficient constitutive expression of certain genes, without needing tyrosine phosphorylation, and phosphorylated STAT1 dimers mediate suppression - rather than activation - of some genes. STATs are present in the cytoplasm of untreated cells in multiprotein complexes, which might aid in their nuclear translocation and differential binding to DNA, thus contributing to the specificity of STAT action. This review explores the diverse protein-protein interactions that underlie the multiple functions of the STATs.

Animals↗

PubMed2000

Transcriptional regulation through Mediator-like coactivators in yeast and metazoan cells.

A novel multiprotein complex has recently been identified as a coactivator for transcriptional control of protein-encoding genes by RNA polymerase II in higher eukaryotic cells. This complex is evolutionarily related to the Mediator complex from yeast and, on the basis of its structural and functional characteristics, promises to be a key target of diverse regulatory circuits.

Animals↗

PubMed2001

The histone fold is a key structural motif of transcription factor TFIID.

Transcription factor TFIID is a multiprotein complex composed of the TATA binding protein and its associated factors, and is required for accurate and regulated initiation of transcription by RNA polymerase II. The subunit composition of this factor is highly conserved from yeast to mammals. X-ray crystallography and biochemical experiments have shown that the histone fold motif mediates many of the subunit interactions within this complex. These results, together with electron microscopy and yeast genetics, provide insights into the overall organization of this complex.

Amino Acid Sequence↗

PubMed2001

Chromatin unfolding and activation by HMGN(*) chromosomal proteins.

The high mobility group N (HMGN) proteins are a family of nuclear proteins that binds to nucleosomes, changes the architecture of chromatin, and enhances transcription and replication from chromatin templates. The intracellular organization of the HMGN (previously known as HMG-14/17) proteins is dynamic and is related to both cell-cycle and transcriptional events. These proteins roam the nucleus, perhaps as part of multiprotein complexes, and their target interactions are modulated by posttranslational modifications. Functional studies on HMGN proteins provide insights into the molecular mechanisms by which structural proteins affect DNA-dependent activities in the context of chromatin.

Amino Acid Sequence↗

PubMed1998

Mechanistic parallels between DNA replication, recombination and transcription.

The multiprotein complexes that mediate replication, transcription and homologous recombination in eukaryotic cells face many of the same molecular challenges. These include the recognition of DNA sites embedded in large chromatinized genomes, the denaturation of duplex DNA, and partial dissociation and reassociation at different stages of the catalytic cycle. Therefore, it is not surprising that several steps in the respective catalytic cycles are strikingly similar at the DNA level and may proceed by similar mechanisms. Some of these relationships are reviewed here. It is argued that speculation based on such 'crosspathway' comparisons may be a valuable paradigm for the design of new experiments.

DNA Replication↗

PubMed1998

DNA end-joining: from yeast to man.

DNA non-homologous end-joining (NHEJ) is a crucial process that has been conserved highly throughout eukaryotic evolution. At its heart is a multiprotein complex containing the KU70-KU80 heterodimer. Recent work has identified additional proteins involved in this pathway, providing insights into the mechanism of NHEJ and revealing exciting links with the control of transcription, telomere length and chromatin structure.

Antigens, Nuclear↗

PubMed2000

The many HATs of transcription coactivators.

Histone acetylation is closely linked to gene transcription. The identification of histone acetyltransferases (HATs) and the large multiprotein complexes in which they reside has yielded important insights into how these enzymes regulate transcription. The demonstration that HAT complexes interact with sequence-specific activator proteins illustrates how these complexes target specific genes. In addition to histones, some HATs can acetylate non-histone proteins suggesting multiple roles for these enzymes.

Acetyltransferases↗

PubMed1998

Protein cross-linking mediated by metalloporphyrins.

A biomimetic protein cross-linking reaction is described which employs oxidatively-activated manganese and iron porphyrins as the reactive species. A wide range of proteins cross-link under these conditions, but only if they are intimately associated in solution. The reaction is rapid, efficient, and will be useful for the suprastructural analysis of multiprotein complexes.

Chelating Agents↗

PubMed1997

The structure of an energy-coupling protein from bacteria, IIBcellobiose, reveals similarity to eukaryotic protein tyrosine phosphatases.

BACKGROUND: . The bacterial phosphoenolpyruvate-dependent phosphotransferase system (PTS) mediates the energy-driven uptake of carbohydrates and their concomitant phosphorylation. In addition, the PTS is intimately involved in the regulation of a variety of metabolic and transcriptional processes in the bacterium. The multiprotein PTS consists of a membrane channel and at least four cytoplasmic proteins or protein domains that sequentially transfer a phosphoryl group from phosphoenolpyruvate to the transported carbohydrate. Determination of the three-dimensional structure of the IIB enzymes within the multiprotein complex would provide insights into the mechanisms by which they promote efficient transport by the membrane channel IIC protein and phosphorylate the transported carbohydrate on the inside of the cell. RESULTS: . The crystal structure of the IIB enzyme specific for cellobiose, IIBcellobiose (molecular weight 11.4 kDa), has been determined to a resolution of 1.8 and refined to an R factor of 18.7% (Rfree of 24. 1%). The enzyme consists of a single four-stranded parallel beta sheet flanked by helices on both sides. The phosphorylation site (Cys 10) is located at the C-terminal end of the first beta strand. No positively charged residues, which could assist in phosphoryl-transfer, can be found in or near the active site. The fold of IIBcellobiose is remarkably similar to that of the mammalian low molecular weight protein tyrosine phosphatases. CONCLUSIONS: . A comparison between IIBcellobiose and the structurally similar low molecular weight protein tyrosine phosphatases provides insight into the mechanism of the phosphoryltransfer reactions in which IIBcellobiose is involved. The differences in tertiary structure and active-site composition between IIBcellobiose and the glucose-specific IIBglucose give a structural explanation why the carbo-hydrate-specific components of different families cannot complement each other.

Animals↗

PubMed2003

The DNA synthesome: its potential as a novel in vitro model system for studying S-phase specific anticancer agents.

A considerable effort is being made to discover more effective anticancer agents and to develop rapid, accurate, and reliable methods for evaluating the usefulness of the new compounds and analyzing their mechanisms of action. In this regard, our laboratory was the first to report the isolation, characterization, and extensive purification of an intact, stable, and fully functional mammalian cell multiprotein complex, which we designated the DNA synthesome. The DNA synthesome has been isolated from a wide variety of mammalian cells as well as from tissues and has been shown to be fully competent to support SV40 origin-specific and large T antigen-dependent DNA replication in vitro. In this article we will review the utilization of the DNA synthesome as a powerful in vitro model system for analyzing the mechanism of action of S-phase specific anticancer agents.

Antineoplastic Agents↗

PubMed2001

Novel glucocorticoid receptor coactivator effector mechanisms.

Glucocorticoids regulate numerous distinct physiological processes, most of which rely on the ability of the hormone-bound glucocorticoid receptor (GR) to change the expression of target genes in a cell- and promoter-dependent manner. The transcriptional activity of GR depends on coactivators that regulate transcription by remodeling chromatin or by facilitating the recruitment of the basal transcriptional machinery. Coactivators are often part of multiprotein complexes that are not specific for GR but also mediate the activity of other nuclear receptors (NRs) and unrelated transcription factors. Surprisingly, recent results reveal that the activity of coactivators might contribute to the receptor, promoter and cell specificity of NR action. The emerging picture shows coactivators as flexible, but precise, coordinators of complex and dynamic networks, in which transcriptional regulation by GR and other NRs is linked to other signaling pathways.

Animals↗

PubMed2003

In vitro analysis of RNA interference in Drosophila melanogaster.

Double-stranded RNA (dsRNA) triggers the destruction of mRNA sharing sequence with the dsRNA, a phenomenon termed RNA interference (RNAi). The dsRNA is converted by endonucleolytic cleavage into 21- to 23-nt small interfering RNAs (siRNAs), which direct a multiprotein complex, the RNA-induced silencing complex to cleave RNA complementary to the siRNA. RNAi can be recapitulated in vitro in lysates of syncytial blastoderm Drosophila embryos. These lysates reproduce all of the known steps in the RNAi pathway in flies and mammals. Here we explain how to prepare and use Drosophila embryo lysates to dissect the mechanism of RNAi.

Animals↗

PubMed2003

A core-weighted fitting method for docking atomic structures into low-resolution maps: application to cryo-electron microscopy.

Cryo-electron microscopy of "single particles" is a powerful method to analyze structures of large macromolecular assemblies that are not amenable to investigation by traditional X-ray crystallographic methods. A key step in these studies is to obtain atomic interpretations of multiprotein complexes by fitting atomic structures of individual components into maps obtained from electron microscopic data. Here, we report the use of a "core-weighting" method, combined with a grid-threading Monte Carlo (GTMC) approach for this purpose. The "core" of an individual structure is defined to represent the part where the density distribution is least likely to be altered by other components that comprise the macromolecular assembly of interest. The performance of the method has been evaluated by its ability to determine the correct fit of (i) the alpha-chain of the T-cell receptor variable domain into a simulated map of the alphabeta complex at resolutions between 5 and 40 A, and (ii) the E2 catalytic domain of the pyruvate dehydrogenase into an experimentally determined map, at 14 A resolution, of the icosahedral complex formed by 60 copies of this enzyme. Using the X-ray structures of the two test cases as references, we demonstrate that, in contrast to more traditional methods, the combination of the core-weighting method and the grid-threading Monte Carlo approach can identify the correct fit reliably and rapidly from the low-resolution maps that are typical of structures determined with the use of single-particle electron microscopy.

Animals↗

PubMed2002

Factor Va increases the affinity of factor Xa for prothrombin: a binding study using a novel photoactivable thiol-specific fluorescent probe.

The multiprotein complex of factor Xa, factor Va, and prothrombin efficiently generates the blood-clotting agent, thrombin. Here, the formation of the factor Xa*prothrombin complex and the effects of factor Va on this complex were examined using a photoactivable thiol-specific fluorescent probe (LWB), which was synthesized and incorporated into the active site of factor Xa. The use of fluorescent LWB illustrated that factor Xa has an increased affinity for prothrombin in the presence of factor Va. Further exposure of these components to UV light resulted in a specific photocrosslinking of LWB-factor Xa to prothrombin, suggesting a physical association between these proteins. These data demonstrate that LWB can successfully function both as a spectroscopic probe and as a photocrosslinking reagent for studying protein-protein interactions.

Cross-Linking Reagents↗

PubMed1998

The Drosophila Polycomb group gene pleiohomeotic encodes a DNA binding protein with homology to the transcription factor YY1.

Genes of the Polycomb group (PcG) of Drosophila encode proteins necessary for the maintenance of transcriptional repression of homeotic genes. PcG proteins are thought to act by binding as multiprotein complexes to DNA through Polycomb group response elements (PREs); however, specific DNA binding has not been demonstrated for any of the PcG proteins. We have identified a sequence-specific DNA binding protein that interacts with a PRE from the Drosophila engrailed gene. This protein (PHO) is a homolog of the ubiquitous mammalian transcription factor Yin Yang-1 and is encoded by pleiohomeotic, a known member of the PcG. We propose that PHO acts to anchor PcG protein complexes to DNA.

Amino Acid Sequence↗

PubMed2004

Antiviral protein Ski8 is a direct partner of Spo11 in meiotic DNA break formation, independent of its cytoplasmic role in RNA metabolism.

Meiotic recombination initiates with double-strand breaks (DSBs) catalyzed by Spo11 in conjunction with accessory proteins whose roles are not understood. Two-hybrid analysis reveals a network of interactions connecting the yeast DSB proteins to one another. Of these proteins, Ski8 was known to function in cytoplasmic RNA metabolism, suggesting that its role in recombination might be indirect. However, obligate partners of Ski8 in RNA metabolism are dispensable for recombination and Ski8 relocalizes to the nucleus and associates with chromosomes specifically during meiosis. Interaction of Ski8 with Spo11 is essential for DSB formation and Ski8 relocalization. Thus, Ski8 plays distinct roles in RNA metabolism and, as a direct partner of Spo11, in DSB formation. Ski8 works with Spo11 to recruit other DSB proteins to meiotic chromosomes, implicating Ski8 as a scaffold protein mediating assembly of a multiprotein complex essential for DSB formation.

Chromatin↗

PubMed2003

The COP9 signalosome-like complex in S. cerevisiae and links to other PCI complexes.

The COP9 signalosome (CSN), the lid subcomplex of the proteasome and translational initiation factor 3 (eIF3) share structural similarities and are often referred to as the PCI family of complexes. In multicellular eukaryotes, the CSN is highly conserved as an 8-subunit complex but in Saccharomyces cerevisiae the complex is rather divergent. We further characterize the composition and properties of the CSN in budding yeast and its interactions with these related complexes. Using the generalized profile method we identified CSN candidates, four with PCI domains: Csn9, Csn10, Pci8/Csn11, and Csn12, and one with an MPN domain, Csn5/Rri1. These proteins and an additional interactor, Csi1, were tested for pairwise interactions by yeast two-hybrid and were found to form a cluster surrounding Csn12. Csn5 and Csn12 cofractionate in a complexed form with an apparent molecular weight of roughly 250kDa. However, Csn5 migrates as a monomer in Deltacsn12 supporting the pivotal role of Csn12 in stabilizing the complex. Confocal fluorescence microscopy detects GFP-tagged Csn5 preferentially in the nucleus, whereas in absence of Csn12, Csn10, Pci8/Csn11, or Csi1, Csn5 is delocalized throughout the cell, indicating that multiple subunits are required for nuclear localization of Csn5. Two CSN subunits, Csn9 and Csi1, interact with the proteasome lid subunit Rpn5. Pci8/Csn11 has previously been shown to interact with eIF3. Together, these results point to a network of interactions between these three structurally similar, yet functionally diverse, complexes.

Amino Acid Sequence↗