Inhibition of antigen presentation by the glycine/alanine repeat domain is not conserved in simian homologues of Epstein-Barr virus nuclear antigen 1.
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Most humans and Old World nonhuman primates are infected for life with Epstein-Barr virus (EBV) or closely related gammaherpesviruses in the same lymphocryptovirus (LCV) subgroup. Several potential strategies for immune evasion and persistence have been proposed based on studies of EBV infection in humans, but it has been difficult to test their actual contribution experimentally. Interest has focused on the EBV nuclear antigen 1 (EBNA1) because of its essential role in the maintenance and replication of the episomal viral genome in latently infected cells and because EBNA1 endogenously expressed in these cells is protected from presentation to the major histocompatibility complex class-I restricted cytotoxic T-lymphocyte (CTL) response through the action of an internal glycine-alanine repeat (GAR). Given the high degree of biologic conservation among LCVs which infect humans and Old World primates, we hypothesized that strategies essential for viral persistence would be well conserved among viruses of this subgroup. We show that the rhesus LCV EBNA1 shares sequence homology with the EBV and baboon LCV EBNA1 and that the rhesus LCV EBNA1 is a functional homologue for EBV EBNA1-dependent plasmid maintenance and replication. Interestingly, all three LCVs possess a GAR domain, but the baboon and rhesus LCV EBNA1 GARs fail to inhibit antigen processing and presentation as determined by using three different in vitro CTL assays. These studies suggest that inhibition of antigen processing and presentation by the EBNA1 GAR may not be an essential mechanism for persistent infection by all LCV and that other mechanisms may be important for immune evasion during LCV infection. (+info)
Cutting edge: identification of novel T cell epitopes in Lol p5a by computational prediction.
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Although atopic allergy affects +info)
Myotactin, a novel hypodermal protein involved in muscle-cell adhesion in Caenorhabditis elegans.
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In C. elegans, assembly of hypodermal hemidesmosome-like structures called fibrous organelles is temporally and spatially coordinated with the assembly of the muscle contractile apparatus, suggesting that signals are exchanged between these cell types to position fibrous organelles correctly. Myotactin, a protein recognized by monoclonal antibody MH46, is a candidate for such a signaling molecule. The antigen, although expressed by hypodermis, first reflects the pattern of muscle elements and only later reflects the pattern of fibrous organelles. Confocal microscopy shows that in adult worms myotactin and fibrous organelles show coincident localization. Further, cell ablation studies show the bodywall muscle cells are necessary for normal myotactin distribution. To investigate myotactin's role in muscle-hypodermal signaling, we characterized the myotactin locus molecularly and genetically. Myotactin is a novel transmembrane protein of approximately 500 kd. The extracellular domain contains at least 32 fibronectin type III repeats and the cytoplasmic domain contains unique sequence. In mutants lacking myotactin, muscle cells detach when embryonic muscle contraction begins. Later in development, fibrous organelles become delocalized and are not restricted to regions of the hypodermis previously contacted by muscle. These results suggest myotactin helps maintain the association between the muscle contractile apparatus and hypodermal fibrous organelles. (+info)
Mapping the binding domains involved in the interaction between the Plasmodium falciparum knob-associated histidine-rich protein (KAHRP) and the cytoadherence ligand P. falciparum erythrocyte membrane protein 1 (PfEMP1).
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Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) clusters at electron-dense knob-like structures on the surface of malaria-infected red blood cells and mediates their adhesion to the vascular endothelium. In parasites lacking knobs, vascular adhesion is less efficient, and infected red cells are not able to immobilize successfully under hemodynamic flow conditions even though PfEMP1 is still present on the exterior of the infected red cell. We examined the interaction between the knob-associated histidine-rich protein (KAHRP), the parasite protein upon which knob formation is dependent, and PfEMP1, and we show evidence of a direct interaction between KAHRP and the cytoplasmic region of PfEMP1 (VARC). We have identified three fragments of KAHRP which bind VARC. Two of these KAHRP fragments (K1A and K2A) interact with VARC with binding affinities (K(D(kin))) of 1 x 10(-7) M and 3.3 x 10(-6) M respectively, values comparable to those reported previously for protein-protein interactions in normal and infected red cells. Further experiments localized the high affinity binding regions of KAHRP to the 63-residue histidine-rich and 70-residue 5' repeats. Deletion of these two regions from the KAHRP fragments abolished their ability to bind to VARC. Identification of the critical domains involved in interaction between KAHRP and PfEMP1 may aid development of new therapies to prevent serious complications of P. falciparum malaria. (+info)
A capping domain for LRR protein interaction modules.
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Leucine-rich repeats (LRR) are protein interaction modules which are present in a large number of proteins with diverse functions. We describe here a novel motif (16-19 residues) downstream of the last, incomplete, LRR in a subfamily of LRR proteins. In the U2A' spliceosomal protein, this motif is folded into a cap that shields the hydrophobic core of the LRRs from the solvent. Modelling of the LRR-cap in the imidazoline-1 candidate receptor, using the known structure of U2A' as template, showed a conservation of the basic structural features. (+info)
Cloning, tissue distribution, subcellular localization and overexpression of murine histidine-rich Ca2+ binding protein.
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The histidine-rich Ca2+ binding protein (HRC) resides in the sarcoplasmic reticulum of muscle and binds Ca2+. Since Ca2+ concentrations can regulate gene expression via calcineurin, the mouse homologue of HRC (mHRC) was isolated and characterized. mHRC was detected in muscle progenitor cells, in primary clonal thymic tumors and a tumor cell line, suggesting a broader role for mHRC than in Ca2+ storage during muscle contraction. mHRC was present in the perinuclear region of myoblasts. To examine if it can regulate gene expression, mHRC was overexpressed in cells differentiating into cardiac and skeletal muscle. mHRC had no effect on cardiogenesis or myogenesis. Therefore, if mHRC plays a role in the regulation of gene expression during cellular differentiation, it does not appear to be either rate-limiting or inhibitory. (+info)
Role for yeast inhibitor of apoptosis (IAP)-like proteins in cell division.
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Inhibitors of apoptosis (IAPs) are a family of proteins that bear baculoviral IAP repeats (BIRs) and regulate apoptosis in vertebrates and Drosophila melanogaster. The yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe both encode a single IAP, designated BIR1 and bir1, respectively, each of which bears two BIRs. In rich medium, BIR1 mutant S. cerevisiae underwent normal vegetative growth and mitosis. Under starvation conditions, however, BIR1 mutant diploids formed spores inefficiently, instead undergoing pseudohyphal differentiation. Most spores that did form failed to survive beyond two divisions after germination. bir1 mutant S. pombe spores also died in the early divisions after spore germination and became blocked at the metaphase/anaphase transition because of an inability to elongate their mitotic spindle. Rather than inhibiting caspase-mediated cell death, yeast IAP proteins have roles in cell division and appear to act in a similar way to the IAPs from Caenorhabditis elegans and the mammalian IAP Survivin. (+info)
Roles of the C terminus of Armadillo in Wingless signaling in Drosophila.
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Drosophila melanogaster Armadillo and its vertebrate homolog beta-catenin play multiple roles during development. Both are components of cell-cell adherens junctions and both transduce Wingless (Wg)/Wnt intercellular signals. The current model for Wingless signaling proposes that Armadillo binds the DNA-binding protein dTCF, forming a bipartite transcription factor that activates Wingless-responsive genes. In this model, Armadillo's C-terminal domain is proposed to serve an essential role as a transcriptional activation domain. In Xenopus, however, overexpression of C-terminally truncated beta-catenin activates Wnt signaling, suggesting that the C-terminal domain might not be essential. We reexamined the function of Armadillo's C terminus in Wingless signaling. We found that C-terminally truncated mutant Armadillo has a deficit in Wg-signaling activity, even when corrected for reduced protein levels. However, we also found that Armadillo proteins lacking all or part of the C terminus retain some signaling ability if overexpressed, and that mutants lacking different portions of the C-terminal domain differ in their level of signaling ability. Finally, we found that the C terminus plays a role in Armadillo protein stability in response to Wingless signal and that the C-terminal domain can physically interact with the Arm repeat region. These data suggest that the C-terminal domain plays a complex role in Wingless signaling and that Armadillo recruits the transcriptional machinery via multiple contact sites, which act in an additive fashion. (+info)