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81.
Further characterization of the covalent linking reaction of alpha 2-macroglobulin. 总被引:13,自引:5,他引:8 下载免费PDF全文
It is shown that non-proteolytic proteins can become covalently linked to alpha 2M (alpha 2-macroglobulin) during its reaction with proteinases, and that this probably occurs by the mechanism that leads to the covalent linking of proteinases described previously [Salvesen & Barrett (1980) Biochem. J. 187, 695-701]. The covalent linking of trypsin was at least partly dependent on the presence of unblocked lysine side chains on the protein. The covalent linking of proteinases was inhibited by nucleophiles of low Mr, and these compounds were themselves linked to alpha 2M in a molar ratio approaching one per quarter subunit. Peptide "mapping" indicated that the site of proteinase-mediated incorporation of the amines was the same as that at which methylamine is incorporated in the absence of a proteinase. The nucleophile-reactive site revealed in alpha 2M after reaction with a proteinase was shown to decay with a t1/2 of 112 s, at pH 7.5. After the reaction with a proteinase or with methylamine, a free thiol group was detectable on each subunit of alpha 2M. We propose that the site for incorporation of methylamine in each subunit is a thiol ester, which in S-alpha 2M (the electrophoretically "slow" form) is sterically shielded from reaction with large nucleophiles, but is revealed as a highly reactive group, free from steric hindrance, after the proteolytic cleavage. We have designated the activated species of the molecule "alpha 2M". 相似文献
82.
Hydroxyurea was used to study the proliferation rate of haemopoietic stem cells (CFUJ in normal mice, after irradiation or transplantation into irradiated recipients. It was demonstrated that the proliferation rate of endogenous CFUS (endo-CFU,) and exogenous CFUS (exo-CFUs) are identical. After irradiation (650 R) the surviving endo-CFUs begin to proliferate immediately. By contrast exo-CFU, transplanted into the irradiated recipient mouse (850 R), begin to proliferate only after about 30 hr. However, injection of isoproterenol (which stimulates adenyl cyclase) or dibutyryl cyclic adenosine 3′,5′-monophosphate shortly after marrow cell graft, triggers the transplanted CFUS into cell cycle as shown by an almost immediately increased sensitivity to hydroxyurea. Isoproterenol is capable of inducing DNA synthesis also in stem cells of normal mice but it takes about 20 hr before CFU, become to be increasingly sensitive to hydroxyurea. 相似文献
83.
Morphometric and cytological data were used to test the variation within the apomictic hybrid Sorbus meinichii from its type locality, in the Moster area, Bømlo in Sunnhordland, Norway. A lectotype is selected for the name. A total of 36 morphological characters were measured on leaves, stomata, flowers, pollen, fruits and seeds, from randomly selected S. meinichii individuals. In the field the material was classified into two groups, one including individuals of generally larger dimensions of leaves and fruits than the other. The preliminary classification was subsequently tested by a multivariate analysis of several characters, substantiating the existence of two morphs in the population at the type locality of S. meinichii , one corresponding to the selected lectotype. Assessment of the nature and taxonomic rank of these two morphs must await further studies. Cytological studies showed both forms of S. meinichii to be triploid, with 2n=51 chromosomes. The taxonomic separation of S. teodorii from S. meinichii on the basis of ploidy level is therefore not corroborated. Sorbus meinichii s. lat. was shown to be intermediate between its supposed parents, S. aucuparia and S. hybrida , in several leaf characters. All of the variation within the S. aucuparia × S. hybrida-complex in Fennoscandia is better included in one aggregate species Sorbus meinichii according to the present state of knowledge. 相似文献
84.
Structural basis for the inhibition of caspase-3 by XIAP 总被引:63,自引:0,他引:63
Riedl SJ Renatus M Schwarzenbacher R Zhou Q Sun C Fesik SW Liddington RC Salvesen GS 《Cell》2001,104(5):791-800
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors. 相似文献
85.
Katarzyna Pustelny Michal Zdzalik Natalia Stach Justyna Stec-Niemczyk Przemyslaw Cichon Anna Czarna Grzegorz Popowicz Pawel Mak Marcin Drag Guy S. Salvesen Benedykt Wladyka Jan Potempa Adam Dubin Grzegorz Dubin 《The Journal of biological chemistry》2014,289(22):15544-15553
Staphylococcal SplB protease belongs to the chymotrypsin family. Chymotrypsin zymogen is activated by proteolytic processing at the N terminus, resulting in significant structural rearrangement at the active site. Here, we demonstrate that the molecular mechanism of SplB protease activation differs significantly and we characterize the novel mechanism in detail. Using peptide and protein substrates we show that the native signal peptide, or any N-terminal extension, has an inhibitory effect on SplB. Only precise N-terminal processing releases the full proteolytic activity of the wild type analogously to chymotrypsin. However, comparison of the crystal structures of mature SplB and a zymogen mimic show no rearrangement at the active site whatsoever. Instead, only the formation of a unique hydrogen bond network, distant form the active site, by the new N-terminal glutamic acid of mature SplB is observed. The importance of this network and influence of particular hydrogen bond interactions at the N terminus on the catalytic process is demonstrated by evaluating the kinetics of a series of mutants. The results allow us to propose a consistent model where changes in the overall protein dynamics rather than structural rearrangement of the active site are involved in the activation process. 相似文献
86.
Ján Lí?KA Július BRTKO Michal DUBOVICKY Dana MACEJOVá Viktória KISSOVá ?tefan POLáK Eduard UJHáZY 《Experimental Animals》2016,65(1):1-9
The mammary gland is a dynamic organ that undergoes structural and functional changes
associated with growth, reproduction, and post-menopausal regression. The postnatal
transformations of the epithelium and stromal cells of the mammary gland may contribute to
its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of
humans and similarly of rodents in association with their development is believed to be
partly explained by proliferative activity together with lesser degree of differentiation,
but it is not completely understood how the virgin gland retains its higher susceptibility
to carcinogenesis. During its developmental cycle, the mammary gland displays many of the
properties associated with breast cancer. An early first full-term pregnancy may have a
protective effect. Rodent models are useful for investigating potential breast
carcinogens. The purpose of this review is to help recognizing histological appearance of
the epithelium and the stroma of the normal mammary gland in rats, and throughout its
development in relation to tumorigenic potential. 相似文献
87.
Hanne Haslene-Hox Eystein Oveland Kathrine Woie Helga B. Salvesen Helge Wiig Olav Tenstad 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(11):2347-2359
We aimed to identify differentially expressed proteins in interstitial fluid from ovarian cancer employing multiple fractioning and high resolution mass spectrometry-based proteomic analysis, and asked whether specific proteins that may serve as biomarker candidates or therapeutic targets could be identified. High throughput proteomics was conducted on immunodepleted and fractioned interstitial fluid from pooled samples of ovarian carcinomas, using endometrial carcinomas and healthy ovarian tissue as controls. Differential analysis revealed the up-regulation of extracellular proteasomes in tumor interstitial fluid compared to the healthy control. Moreover, a number of differentially expressed proteins in interstitial fluid from ovarian carcinomas compared with control tissues were identified. Detection of proteasome 20S related proteins in TIF compared to IF from healthy tissue indicates that the 20S proteasome can have a role in the tumor microenvironment. Six selected proteins, CEACAM5, FREM2, MUC5AC, TFF3, PYCARD and WDR1, were independently validated in individual tumor lysates from ovarian carcinomas by multiple reaction monitoring initiated detection and sequence analysis, Western blot and/or selected reaction monitoring. Quantification of specific proteins revealed substantial heterogeneity between individual samples. Nevertheless, WD repeat-containing protein 1 was confirmed as being significantly overexpressed in interstitial fluid from ovarian carcinomas compared to healthy ovarian tissue by Orbitrap analysis of individual native interstitial fluid from ovarian and endometrial carcinomas and healthy ovarian tissue. We suggest that this protein should be explored as a therapeutic target in ovarian carcinomas. This article is part of a Special Issue entitled: An Updated Secretome. 相似文献
88.
89.
Békés M Prudden J Srikumar T Raught B Boddy MN Salvesen GS 《The Journal of biological chemistry》2011,286(12):10238-10247
SUMOylation of proteins is a cyclic process that requires both conjugation and deconjugation of SUMO moieties. Besides modification by a single SUMO, SUMO chains have also been observed, yet the dynamics of SUMO conjugation/deconjugation remain poorly understood. Using a non-deconjugatable form of SUMO we demonstrate the underappreciated existence of SUMO chains in vivo, we highlight the importance of SUMO deconjugation, and we demonstrate the highly dynamic nature of the SUMO system. We show that SUMO-specific proteases (SENPs) play a crucial role in the dynamics of SUMO chains in vivo by constant deconjugation. Preventing deSUMOylation in Schizosaccharomyces pombe results in slow growth and a sensitivity to replication stress, highlighting the biological requirement for deSUMOylation dynamics. Furthermore, we present the mechanism of SUMO chain deconjugation by SENPs, which occurs via a stochastic mechanism, resulting in cleavage anywhere within a chain. Our results offer mechanistic insights into the workings of deSUMOylating proteases and highlight their importance in the homeostasis of (poly)SUMO-modified substrates. 相似文献
90.
ELIŠKA ZÁVESKÁ TOMÁŠ FÉR OTAKAR ŠÍDA JANA LEONG‐ŠKORNIČKOVÁ MAMYIL SABU KAROL MARHOLD 《Botanical journal of the Linnean Society. Linnean Society of London》2011,165(4):388-401
The relationships between genome size and the systematic and evolutionary patterns in vascular plants are equivocal, although a close relationship between genome size and evolutionary patterns has been previously reported. However, several studies have also revealed the dynamic nature of genome size evolution and its considerable ‘ups’ and ‘downs’. Thus, in this study, the phylogenetic relationships among three previously revealed genome size groups and among species of the highly polyploid genus Curcuma were evaluated using AFLP. Our results suggest two main lineages within Indian Curcuma reflecting evolution of genome size. The first one includes hexaploids and higher polyploids of the previously recognized genome size group I, and the second one includes mainly hexaploids of genome size groups II and III. Within genome size group I, relationships among species seem to be influenced by reticulate evolution and higher polyploids are likely to be of allopolyploid origin. Reproductive systems in Indian Curcuma vary considerably among ploidy levels and these differences considerably affect morphological and genetic variation. In general, clonally reproducing species are expected to exhibit low genotypic diversity, but, at the same time, species of allopolyploid origin are expected to maintain higher levels of heterozygosity compared with their progenitors. We investigated intra‐populational genetic variability in Curcuma spp. to evaluate whether mode of reproduction or ploidy represent the main factor influencing the degree of genetic diversity. We found that hexaploid species exhibited significantly higher genetic diversity than higher polyploids (9x, 15x). Our results suggest that this genetic diversity pattern is largely influenced by the mode of reproduction, as higher polyploids reproduce exclusively vegetatively, whereas hexaploids reproduce mainly sexually. © 2011 The Linnean Society of London, Botanical Journal of the Linnean Society, 2011, 165 , 388–401. 相似文献