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61.
Nishikawa H Ooka S Sato K Arima K Okamoto J Klevit RE Fukuda M Ohta T 《The Journal of biological chemistry》2004,279(6):3916-3924
The breast and ovarian cancer suppressor BRCA1 acquires significant ubiquitin ligase activity when bound to BARD1 as a RING heterodimer. Although the activity may well be important for the role of BRCA1 as a tumor suppressor, the biochemical consequence of the activity is not yet known. Here we report that BRCA1-BARD1 catalyzes Lys-6-linked polyubiquitin chain formation. K6R mutation of ubiquitin dramatically reduces the polyubiquitin products mediated by BRCA1-BARD1 in vitro. BRCA1-BARD1 preferentially utilizes ubiquitin with a single Lys residue at Lys-6 or Lys-29 to mediate autoubiquitination of BRCA1 in vivo. Furthermore, mass spectrometry analysis identified the Lys-6-linked branched ubiquitin fragment from the polyubiquitin chain produced by BRCA1-BARD1 using wild type ubiquitin. The BRCA1-BARD1-mediated Lys-6-linked polyubiquitin chains are deubiquitinated by 26 S proteasome in vitro, whereas autoubiquitinated CUL1 through Lys-48-linked polyubiquitin chains is degraded. Proteasome inhibitors do not alter the steady state level of the autoubiquitinated BRCA1 in vivo. Hence, the results indicate that BRCA1-BARD1 mediates novel polyubiquitin chains that may be distinctly edited by 26 S proteasome from conventional Lys-48-linked polyubiquitin chains. 相似文献
62.
Kellar Autumn Devin Jindrich Dale DeNardo Rachel Mueller 《Evolution; international journal of organic evolution》1999,53(2):580-599
Nocturnal geckos are active at body temperatures 10–35°C below the thermal optima for maximum rate of aerobic metabolism of diurnal lizards. Therefore, given ancestral (diurnal) lizard physiology, nocturnality causes a substantial thermal handicap in locomotor performance. In prior studies, we hypothesized that a low minimum cost of locomotion (Cmin) in geckos was an adaptation that increased locomotor endurance capacity at low, nocturnal temperatures. However, Cmin is only part of an integrated system that, in conjunction with the maximum rate of oxygen consumption, sets the maximum speed that can be sustained aerobically (termed the maximum aerobic speed or MAS). We conducted the first phylogenetic analysis of MAS and lizards and found that the greatest changes in MAS, Cmin and (at activity temperatures) in the evolutionary history of lizards all coincided with the evolution of nocturnality in geckos. Geckos active at 15–25°C did not become optimized for nocturnal temperatures, or fully offset the thermal effects of nocturnality by evolving maximal rates of oxygen consumption comparable to diurnal lizards active at 35°C. Geckos did evolve MAS twice that of diurnal lizards running at low temperatures by evolving a remarkably low Cmin. Allometric analysis and phylogenetically independent contrasts of , Cmin, and MAS indicate a 72% evolutionary decrease in , (at activity temperatures) and a 50% evolutionary decrease in Cmin concordant with the evolution of nocturnality in geckos. Experimental measurements show that decreased Cmin in six species of gecko increased MAS by 50–120% compared to diurnal lizards at low temperatures. Thus, geckos sufficiently overcame the near paralyzing effects of nocturnal temperatures, but only offset about 50% of the decrease in MAS resulting from the low maximum rate of oxygen consumption. Although the nocturnal environment remains severely suboptimal, the evolution of a low cost of locomotion in the ancestor of geckos was highly adaptive for nocturnality. We also present a generalized approach to ecophysiological evolution that integrates phylogeny with the causal relationships among environment, physiology, and performance capacity. With respect to a clade, two hypotheses are central to our integrative approach: (1) a change of an environmental variable (e.g., temperature) causes a performance handicap; and (2) evolution of a physiological variable (e.g., minimum cost of locomotion [Cmin]) increases performance in the derived environment. To test the hypothesis that evolution of a physiological variable is adaptive in nature, we suggest determining if individuals in nature perform at levels exceeding the performance capacity of their hypothetical ancestors and if this additional performance capacity is due to the evolution of the physiological variable in question. 相似文献
63.
Robinson MW Greig R Beattie KA Lamont DJ Connolly B 《International journal for parasitology》2007,37(2):139-148
The nematodes Trichinella spiralis and Trichinella pseudospiralis are both intracellular parasites of skeletal muscle cells and induce profound alterations in the host cell resulting in a re-alignment of muscle-specific gene expression. While T. spiralis induces the production of a collagen capsule surrounding the host-parasite complex, T. pseudospiralis exists in a non-encapsulated form and is also characterised by suppression of the host inflammatory response in the muscle. These observed differences between the two species are thought to be due to variation in the proteins excreted or secreted (ES proteins) by the muscle larva. In this study, we use a global proteomics approach to compare the ES protein profiles from both species and to identify individual T. pseudospiralis proteins that complement earlier studies with T. spiralis. Following two-dimensional gel electrophoresis, tandem mass spectrometry was used to identify the peptide spots. In many cases identification was aided by the determination of partial peptide sequence from selected mass ions. The T. pseudospiralis spots identified included the major secreted glycoproteins and the secreted 5'-nucleotidase. Furthermore, two major groups of T. spiralis-specific proteins and several T. pseudospiralis-specific proteins were identified. Our results demonstrate the value of proteomics as a tool for the identification of ES proteins that are differentially expressed between Trichinella species and as an aid to identifying key parasite proteins that are involved in the host-parasite interaction. The value of this approach will be further enhanced by data arising out the current T. spiralis genome sequencing project. 相似文献
64.
65.
Esperanza Fernández Mark O Collins Rachel T Uren Maksym V Kopanitsa Noboru H Komiyama Mike D R Croning Lysimachos Zografos J Douglas Armstrong Jyoti S Choudhary Seth G N Grant 《Molecular systems biology》2009,5(1)
The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD‐95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD‐95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage‐dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease. 相似文献
66.
67.
Rachel A. Levin David J. Suggett Matthew R. Nitschke Madeleine J.H. van Oppen Peter D. Steinberg 《The Journal of eukaryotic microbiology》2017,64(5):588-597
Dinoflagellates within the genus Symbiodinium are photosymbionts of many tropical reef invertebrates, including corals, making them central to the health of coral reefs. Symbiodinium have therefore gained significant research attention, though studies have been constrained by technical limitations. In particular, the generation of viable cells with their cell walls removed (termed protoplasts) has enabled a wide range of experimental techniques for bacteria, fungi, plants, and algae such as ultrastructure studies, virus infection studies, patch clamping, genetic transformation, and protoplast fusion. However, previous studies have struggled to remove the cell walls from armored dinoflagellates, potentially due to the internal placement of their cell walls. Here, we produce the first Symbiodinium protoplasts from three genetically and physiologically distinct strains via incubation with cellulase and osmotic agents. Digestion of the cell walls was verified by a lack of Calcofluor White fluorescence signal and by cell swelling in hypotonic culture medium. Fused protoplasts were also observed, motivating future investigation into intra‐ and inter‐specific somatic hybridization of Symbiodinium. Following digestion and transfer to regeneration medium, protoplasts remained photosynthetically active, regrew cell walls, regained motility, and entered exponential growth. Generation of Symbiodinium protoplasts opens exciting, new avenues for researching these crucial symbiotic dinoflagellates, including genetic modification. 相似文献
68.
69.
Age at onset in two common neurodegenerative diseases is genetically controlled 总被引:16,自引:1,他引:16 下载免费PDF全文
Li YJ Scott WK Hedges DJ Zhang F Gaskell PC Nance MA Watts RL Hubble JP Koller WC Pahwa R Stern MB Hiner BC Jankovic J Allen FA Goetz CG Mastaglia F Stajich JM Gibson RA Middleton LT Saunders AM Scott BL Small GW Nicodemus KK Reed AD Schmechel DE Welsh-Bohmer KA Conneally PM Roses AD Gilbert JR Vance JM Haines JL Pericak-Vance MA 《American journal of human genetics》2002,70(4):985-993
To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%–60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases. 相似文献
70.
William Coley Rachel Van Duyne Lawrence Carpio Irene Guendel Kylene Kehn-Hall Sebastien Chevalier Aarthi Narayanan Truong Luu Norman Lee Zachary Klase Fatah Kashanchi 《The Journal of biological chemistry》2010,285(42):31930-31943
MicroRNAs (miRNAs) are a class of small RNA molecules that function to control gene expression and restrict viral replication in host cells. The production of miRNAs is believed to be dependent upon the DICER enzyme. Available evidence suggests that in T lymphocytes, HIV-1 can both suppress and co-opt the host''s miRNA pathway for its own benefit. In this study, we examined the state of miRNA production in monocytes and macrophages as well as the consequences of viral infection upon the production of miRNA. Monocytes in general express low amounts of miRNA-related proteins, and DICER in particular could not be detected until after monocytes were differentiated into macrophages. In the case where HIV-1 was present prior to differentiation, the expression of DICER was suppressed. MicroRNA chip results for RNA isolated from transfected and treated cells indicated that a drop in miRNA production coincided with DICER protein suppression in macrophages. We found that the expression of DICER in monocytes is restricted by miR-106a, but HIV-1 suppressed DICER expression via the viral gene Vpr. Additionally, analysis of miRNA expression in monocytes and macrophages revealed evidence that some miRNAs can be processed by both DICER and PIWIL4. Results presented here have implications for both the pathology of viral infections in macrophages and the biogenesis of miRNAs. First, HIV-1 suppresses the expression and function of DICER in macrophages via a previously unknown mechanism. Second, the presence of miRNAs in monocytes lacking DICER indicates that some miRNAs can be generated by proteins other than DICER. 相似文献