In the budding yeast Saccharomyces cerevisiae, self-recognition and the thereby promoted aggregation of thousands of cells into protective flocs is mediated by a family of cell-surface adhesins, the flocculins (Flo). Based on this social behavior FLO genes fulfill the definition of "greenbeard" genes, which direct cooperation toward other carriers of the same gene. The process of flocculation plays an eminent role in the food industry for the production of beer and wine. However, the precise mode of flocculin-mediated surface recognition and the exact structure of cognate ligands have remained elusive. Here, we present structures of the adhesion domain of a flocculin complexed to its cognate ligands derived from yeast high-mannose oligosaccharides at resolutions up to 0.95 Å. Besides a PA14-like architecture, the Flo5A domain reveals a previously undescribed lectin fold that utilizes a unique DcisD calcium-binding motif for carbohydrate binding and that is widely spread among pro-and eukaryotes. Given the high abundance of high-mannose oligosaccharides in yeast cell walls, the Flo5A structure suggests a model for recognition, where social non-selfinstead of unsocial self-interactions are favored.altruism | molecular recognition | fungal development | atomic resolution S elf-recognition is key to both microbial growth and tissue formation. The molecular basis of this phenomenon is well understood only for a few cases-e.g., during neural differentiation and immune recognition. In the microbial world, the formation of multicellular structures by self-recognition is mediated by specific, surface-exposed adhesins and provides protection and promotes long-term survival, substrate exploration, or host invasion (1, 2). In the budding yeast Saccharomyces cerevisiae, aggregation of vegetative cells is a paradigm for biofilm formation (3, 4) and the evolution of social behavior (5, 6). Self-recognition in this organism is mediated by flocculin proteins, which belong to a family of fungal adhesins that are present in pathogenic yeasts as well (7). The general architecture of flocculins includes an N-terminal A domain corresponding to a lectin-like adhesin domain, a stalk-like, repetitive and highly glycosylated B domain, and a C domain that carries a GPI anchoring site (8). The genome of S. cerevisiae contains at least four functional FLO genes (FLO1, FLO5, FLO9, and FLO10) whose N-terminal A domains are predicted to belong to the PA14-like protein family (9) first described in the anthrax-protective antigen (10). This protein family has been found to be widely distributed among all domains of life including human galactosyltransferases and fibrocystin (9, 11).Flocculins confer dominant, calcium-dependent cell-cell adhesion that can be inhibited by hexoses like mannose (12, 13). This process is known as flocculation and has been exploited for centuries by the brewing industry (14). Flocculin genes also mediate social behavior of S. cerevisiae and have here been found to fulfill the definition of "greenbeard" genes (5, 6). E...
In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2 H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1 H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2 H-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC 50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.
The occurrence of N-glycans with a bisecting GlcNAc modification on glycoproteins has many implications in developmental and immune biology. However, these particular N-glycans are difficult to obtain either from nature or through synthesis. We have developed a flexible and general method for synthesizing bisected N-glycans of the complex type by employing modular TFAc-protected donors for all antennae. The TFAc-protected N-glycans are suitable for the late introduction of a bisecting GlcNAc. This integrated strategy permits for the first time the use of a single approach for multiantennary N-glycans as well as their bisected derivatives via imidates, with unprecedented yields even in a one-pot double glycosylation. With this new method, rare N-glycans of the bisected type can be obtained readily, thereby providing defined tools to decipher the biological roles of bisecting GlcNAc modifications.
We determined the specificity of BTL, a lectin from the red marine alga Bryothamnion triquetrum, toward fucosylated oligosaccharides. BTL showed a strict specificity for the core α1,6-fucosylation, which is an important marker for cancerogenesis and quality control of therapeutical antibodies. The double fucosylation α1,6 and α1,3 was also recognized, but the binding was totally abolished in the sole presence of the α1,3-fucosylation. A more detailed analysis of the specificity of BTL showed a preference for bi- and tri-antennary nonbisected N-glycans. Sialylation or fucosylation at the nonreducing end of N-glycans did not affect the recognition by the lectin. BTL displayed a strong affinity for a core α1,6-fucosylated octasaccharide with a Kd of 12 μM by titration microcalorimetry. The structural characterization of the interaction between BTL and the octasaccharide was obtained by STD-NMR. It demonstrated an extended epitope for recognition that includes the fucose residue, the distal GlcNAc and one mannose residue. Recombinant rBTL was obtained in Escherichia coli and characterized. Its binding properties for carbohydrates were studied using hemagglutination tests and glycan array analysis. rBTL was able to agglutinate rabbit erythrocytes with strong hemagglutination activity only after treatment with papain and trypsin, indicating that its ligands were not directly accessible at the cell surface. The hemagglutinating properties of rBTL confirm the correct folding and functional state of the protein. The results show BTL as a potent candidate for cancer diagnosis and as a reagent for the preparation and quality control of antibodies lacking core α1,6-fucosylated N-glycans.
A patient with a tentorial dural AV fistula causing atypical trigeminal neuralgia (TN) successfully treated by embolization is reported. The patient developed persisting throbbing facial pain in the distribution of the second and third division of the right trigeminal nerve (V2,V3) after a history of typical neuralgia for one year, preceded by a two month spell of TN 6 years previously and accompanied by right-sided pulsatile tinnitus for 10 years. The patient's mother, brother and sister were also said to be affected by typical trigeminal neuralgia.A right-sided dilated vein of Rosenthal due to a dural AV fistula fed by branches of the meningeal, occipital and meningo-hypophyseal trunk of the internal carotid artery was thought to cause trigeminal nerve compression. Complete resolution of symptoms after partial intra-arterial embolization of the main feeding arteries with N-butyroacrylate is described.
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