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111.
The aim of this study was to establish a new tool for screening surface displayed peptide libraries based on the idea that cells expressing an enzyme inhibitor at the surface can be specifically labeled by the target enzyme. For this purpose peptide P15, exhibiting a K(i) value of 0.25 microM toward human cathepsin G, was expressed on the Escherichia coli cell surface by the use of Autodisplay. Purified cathepsin G was coupled to biotin and incubated with cells expressing the inhibitor. After addition of streptavidin-fluorescein isothiocyanate, these cells could be clearly differentiated from control cells by whole-cell fluorescence using flow cytometer analysis. To determine whether this protocol can be used for the sorting of single cells, a mixed population of cells with and without inhibitor was treated accordingly. Single cells were selected by increased fluorescence and sorted using fluorescence-activated cell sorting (FACS). Single cell clones were obtained and subjected to DNA sequence analysis. It turned out that the bacteria selected by this protocol displayed the correct peptide inhibitor at the cell surface. The protocol was then used to screen random peptide libraries, expressed at the cell surface, and a new lead structure for human cathepsin G (IC50 = 11.7 microM) was identified. The new drug discovery tool presented here consists of three steps: (a) surface display of peptide libraries, (b) selection of single cells with inhibiting structures by using the inherent affinity of the target enzyme, and (c) sorting of single cells, which were labeled by FACS. 相似文献
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Summary The modern hadromerid coralline spongeSpirastrella (Acanthochaetetes) wellsi exhibits a unique secondary high-Mg calcite (>19 mol % MgCO3) basal skeleton. The basal skeleton is constructed of bundles of elongated crystals more or less tangentially orientated.
The initial formation of these crystals is controlled by soluble highly acidic aspartic and glutamic-rich (40%) macromolecules.
The skeletal mineralization occurs in four different loci: in the top of the calicles, at the tabulae, on collagenous anchor
fibres, and within closed spaces between the tabulae. The clicle walls are formed on the uppermost top of the basal skeleton
as a continuous process. Based on long term stainings with Ca2+-chelating fluorochroms (calcein, chlorotetracyclines) the growth rate of this sponge is extremely low with ca. 50–100μm/a.
The skeletal formation takes places outside the sponge, within a narrow zone (300–500 nm) between the basopinacoderm and the
mature basal skeleton. The sponge produces thread-like folded templates (‘spaghetti fibres’) of 0,5–2 μm size, the shape controlling
insoluble organic matrix. These templates become mineralized in a first step as MgCO3, then are stretched. A soluble organic matrix is also secreted, and remains are included inside the mineralized skeleton.
This organic matrix consists of in a complex mixture containing small very acidic proteins (5, 13, 31 KD; 40% Asp and Glu
and therefore most probably Ca2+-binding) and high molecular weight glycoproteins among several other organic compounds. The mature crystals are high-Mg calcites.
During calcification large cells with large reserve granules (LCG) are always present in a tight connection with the basopinacoderm.
These cells form also the collagenous anchor fibres. Primary tabulae are formed by a non-collagenous organic sheet. Calcification
happens only when LCG cells are enriched on the organic sheet. Randomly oriented high-Mg calcite crystals are growing on the
collagenous anchor fibres. The same type of the mineralization is observed within the spaces of the tabulae. This particular
case of mineralization is controlled by decaying sponge tissue (ammonification). The δ13C values are in equilibrium with the ambient sea water and vary between +3.2 and +2.8 ‰. The mode of mineralization of the
basal skeleton can be described as biologically induced resp. matrix mediated. 相似文献
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Locking and unlocking of ribosomal motions 总被引:20,自引:0,他引:20
During the ribosomal translocation, the binding of elongation factor G (EF-G) to the pretranslocational ribosome leads to a ratchet-like rotation of the 30S subunit relative to the 50S subunit in the direction of the mRNA movement. By means of cryo-electron microscopy we observe that this rotation is accompanied by a 20 A movement of the L1 stalk of the 50S subunit, implying that this region is involved in the translocation of deacylated tRNAs from the P to the E site. These ribosomal motions can occur only when the P-site tRNA is deacylated. Prior to peptidyl-transfer to the A-site tRNA or peptide removal, the presence of the charged P-site tRNA locks the ribosome and prohibits both of these motions. 相似文献
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Antonia Piazzesi Yiru Wang Joshua Jackson Lena Wischhof Viktoria ZeislerDiehl Enzo Scifo Ina Oganezova Thorben Hoffmann Pablo Gmez Martín Fabio Bertan Chester J J Wrobel Frank C Schroeder Dan Ehninger Kristian Hndler Joachim L Schultze Lukas Schreiber Gerhild van EchtenDeckert Pierluigi Nicotera Daniele Bano 《EMBO reports》2022,23(5)
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Copy number expansions such as amplifications and duplications contribute to human phenotypic variation, promote molecular diversification during evolution, and drive the initiation and/or progression of various cancers. The mechanisms underlying these copy number changes are still incompletely understood, however. We recently demonstrated that transient, limited re-replication from a single origin in Saccharomyces cerevisiae efficiently induces segmental amplification of the re-replicated region. Structural analyses of such re-replication induced gene amplifications (RRIGA) suggested that RRIGA could provide a new mechanism for generating copy number variation by non-allelic homologous recombination (NAHR). Here we elucidate this new mechanism and provide insight into why it is so efficient. We establish that sequence homology is both necessary and sufficient for repetitive elements to participate in RRIGA and show that their recombination occurs by a single-strand annealing (SSA) mechanism. We also find that re-replication forks are prone to breakage, accounting for the widespread DNA damage associated with deregulation of replication proteins. These breaks appear to stimulate NAHR between re-replicated repeat sequences flanking a re-initiating replication origin. Our results support a RRIGA model where the expansion of a re-replication bubble beyond flanking homologous sequences followed by breakage at both forks in trans provides an ideal structural context for SSA–mediated NAHR to form a head-to-tail duplication. Given the remarkable efficiency of RRIGA, we suggest it may be an unappreciated contributor to copy number expansions in both disease and evolution. 相似文献