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41.
Zipper interacting protein kinase (ZIPK, also known as death-associated protein kinase 3 [DAPK3]) is a Ser/Thr kinase that functions in programmed cell death. Since its identification eight years ago, contradictory findings regarding its intracellular localization and molecular mode of action have been reported, which may be attributed to unpredicted differences among the human and rodent orthologs. By aligning the sequences of all available ZIPK orthologs, from fish to human, we discovered that rat and mouse sequences are more diverged from the human ortholog relative to other, more distant, vertebrates. To test experimentally the outcome of this sequence divergence, we compared rat ZIPK to human ZIPK in the same cellular settings. We found that while ectopically expressed human ZIPK localized to the cytoplasm and induced membrane blebbing, rat ZIPK localized exclusively within nuclei, mainly to promyelocytic leukemia oncogenic bodies, and induced significantly lower levels of membrane blebbing. Among the unique murine (rat and mouse) sequence features, we found that a highly conserved phosphorylation site, previously shown to have an effect on the cellular localization of human ZIPK, is absent in murines but not in earlier diverging organisms. Recreating this phosphorylation site in rat ZIPK led to a significant reduction in its promyelocytic leukemia oncogenic body localization, yet did not confer full cytoplasmic localization. Additionally, we found that while rat ZIPK interacts with PAR-4 (also known as PAWR) very efficiently, human ZIPK fails to do so. This interaction has clear functional implications, as coexpression of PAR-4 with rat ZIPK caused nuclear to cytoplasm translocation and induced strong membrane blebbing, thus providing the murine protein a possible adaptive mechanism to compensate for its sequence divergence. We have also cloned zebrafish ZIPK and found that, like the human and unlike the murine orthologs, it localizes to the cytoplasm, and fails to bind the highly conserved PAR-4 protein. This further supports the hypothesis that murine ZIPK underwent specific divergence from a conserved consensus. In conclusion, we present a case of species-specific divergence occurring in a specific branch of the evolutionary tree, accompanied by the acquisition of a unique protein–protein interaction that enables conservation of cellular function. 相似文献
42.
DNA methylation in health, disease, and cancer 总被引:5,自引:0,他引:5
The spatial arrangement and three-dimensional structure of DNA in the nucleus is controlled through the interdigitation of DNA binding proteins such as histones and their modifiers, the Polycomb-Trithorax proteins, and the DNA methyltransferase enzymes. DNA methylation forms the foundation of chromatin and is crucial to epigenetic gene regulation in mammals. Disease pathogenesis mediated through infectious agents, inflammation, aging, or genetic damage often involves changes in gene expression. In particular, cellular transformation coincides with multiple changes in chromatin architecture, many of which appear to affect genome integrity and gene expression. Infectious agents, such as viruses directly affect genome structure and induce methylation of particular sequences to suppress host immune responses. Hyperproliferative tissues such as those in the gastrointestinal tract and colon have been shown to gradually acquire aberrant promoter hypermethylation. Here we review recent findings on altered DNA methylation in human disease, with particular focus on cancer and the increasingly large number of genes subject to tumor-specific promoter hypermethylation and the possible role of aberrant methylation in tumor development. 相似文献
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44.
Adi Yahalom Geula Davidov Sofiya Kolusheva Hadassa Shaked Shiran Barber-Zucker Raz Zarivach Jordan H. Chill 《生物化学与生物物理学报:生物膜》2019,1861(12):183054
BteA, a 69-kDa cytotoxic protein, is a type III secretion system (T3SS) effector in the classical Bordetella, the etiological agents of pertussis and related mammalian respiratory diseases. Like other cytotoxicity-mediating effectors, BteA uses its multifunctional N-terminal domain to target phosphatidylinositol (PI)-rich microdomains in the host membrane. Despite their structural similarity, T3SS effectors exhibit a variable range of membrane interaction modes, and currently only limited structural information is available for the BteA membrane-targeting domain and the molecular mechanisms underlying its function. Employing a synergistic combination of structural methods, here we determine the structure of this functional domain and uncover key molecular determinants mediating its interaction with membranes. Residues 29–121 of BteA form an elongated four-helix bundle packed against two shorter perpendicular helices, the second of which caps the domain in a critical ‘tip motif’. A flexible region preceding the BteA helical bundle contains the characteristic β-motif required for binding its cognate chaperone BtcA. We show that BteA targets PI(4,5)P2-containing lipoprotein nanodiscs and binds a soluble PI(4,5)P2 analog via an extensive positively charged surface spanning its first two helices, and that this interaction is weaker for PI(3,5)P2 and abolished for PI(4)P. We confirmed this model of membrane-targeting by observation of BteA-induced changes in the structure of PI(4,5)P2-containing phospholipid bilayers using small-angle X-ray scattering (SAXS). We also extended these results to a larger BteA domain (residues 1–287), confirming its interaction with bilayers using calorimetry, fluorescence and SAXS methods. This novel view of the structural underpinnings of membrane targeting by BteA is an important step towards a comprehensive understanding of cytotoxicity in Bordetella, as well as interactions of a broad range of pathogens with their respective hosts. 相似文献
45.
Kathleen M. Gorman Esther Meyer Detelina Grozeva Egidio Spinelli Amy McTague Alba Sanchis-Juan Keren J. Carss Emily Bryant Adi Reich Amy L. Schneider Ronit M. Pressler Michael A. Simpson Geoff D. Debelle Evangeline Wassmer Jenny Morton Diana Sieciechowicz Eric Jan-Kamsteeg Alex R. Paciorkowski Manju A. Kurian 《American journal of human genetics》2019,104(5):948-956
46.
Wilms tumor and the WT1 gene 总被引:24,自引:0,他引:24
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48.
The oral dentition and type and number of taste buds (TB) on the lips and in the oropharyngeal cavity were compared by means of SEM in 11 species of cardinal fishes (Apogonidae) belonging to five genera. The occurrence of a dense cover of skin papillae on the lips of some species (e.g., Apogon frenatus), as well as differences in structure of vomer, tongue, and palatinum, expose additional morphological characters important for clarification of the taxonomy of this group of fishes. Differences are also revealed in the type of dentition, such as on the vomer and epi-hypopharyngeal bones. Strong and dense dentition of the anterior part of the oral cavity and a high number of TB on this site in species feeding on larger prey (e.g., Cheilodipterus spp) is compared to the relatively feeble jaw armor and richness of TB on the more pharyngeal site in species feeding on smaller prey (e.g., Apogon angustatus, A. frenatus). In addition to the three types of TB (Types I-III) previously described from various teleost fish, a fourth type (Type IV), comprising very small buds, was found in some cardinal fish (Apogon angustatus, A. frenatus). The various TB are distributed from the lips to the pharyngeal bones, on the breathing valves, tongue, palatinum, and pharyngeal bones; their number and type on the various sites differ in the different species. In all species studied the Types I and II TB, elevated above the surrounding epithelium, dominated the lips and anterior part of mouth, while Types III and IV, which end apically at the level with the epithelium, dominated the more posterior pharyngeal region. The highest number of TB, around 24,600, were found in Fowleria variegata, a typical nocturnal species, and the lowest in the diurnal and crepuscular Apogon cyanosoma (1,660) and Cheilodipterus quinquestriatus (2,400). Differences are also revealed in the type of dentition, such as on the vomer and epi-hypopharyngeal bones. The number of TB increased with growth of the fishes. The differences in the total number of TB and their distribution in the oropharyngeal cavity in the various species indicates possible different mechanisms of foraging and food-recognition. 相似文献
49.
INO80 and gamma-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair 总被引:31,自引:0,他引:31
Morrison AJ Highland J Krogan NJ Arbel-Eden A Greenblatt JF Haber JE Shen X 《Cell》2004,119(6):767-775
50.
Drosophila proprioceptors (chordotonal organs) are structured as a linear array of four lineage-related cells: a neuron, a glial cell, and two accessory cells, called cap and ligament, between which the neuron is stretched. To function properly as stretch receptors, chordotonal organs must be stably anchored at both edges. The cap cells are anchored to the cuticle through specialized lineage-related attachment cells. However, the mechanism by which the ligament cells at the other edge of the organ attach is not known. Here, we report the identification of specialized attachment cells that anchor the ligament cells of pentascolopidial chordotonal organs (lch5) to the cuticle. The ligament attachment cells are recruited by the approaching ligament cells upon reaching their attachment site, through an EGFR-dependent mechanism. Molecular characterization of lch5 attachment cells demonstrated that they share significant properties with Drosophila tendon cells and with mammalian proprioceptive organs. 相似文献