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Molinari AJ Trybulski EJ Bagli J Croce S Considine J Qi J Ali K Demaio W Lihotz L Cochran D 《Bioorganic & medicinal chemistry letters》2007,17(21):5796-5800
Small molecule agonists and antagonists of the V(2)-vasopressin receptor have been discovered and have undergone clinical trials. In conjunction with these discovery programs, the synthesis and biological testing of various metabolites associated with these clinical targets were actively pursued. We now report the results of our synthetic efforts and the corresponding biological data generated for several of the metabolites of WAY-151932 and CL-347985 (Lixivaptan). 相似文献
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Coughlan CM Walker JL Cochran JC Wittrup KD Brodsky JL 《The Journal of biological chemistry》2004,279(15):15289-15297
The rate-limiting step in protein secretion is folding, which occurs in the endoplasmic reticulum (ER) lumen, and almost all secreted proteins contain disulfide bonds that form in the ER and stabilize the native state. Secreted proteins unable to fold may aggregate or they may be subject to ER-associated protein degradation. To examine the fate of aberrant forms of a well characterized, disulfide-bonded secreted protein, we expressed bovine pancreatic trypsin inhibitor in yeast. Bovine pancreatic trypsin inhibitor is a single domain, 58-amino acid polypeptide containing three disulfide bonds, and yeast cells secrete the wild type protein. In contrast, the Y35L mutant, which folds rapidly but is unstable, remains soluble and is not secreted. Surprisingly, the proteolysis of Y35L is unaffected in yeast containing mutations in genes encoding factors required for ER-associated protein degradation and is stable if artificially retained in the ER. Rather, Y35L is diverted from the Golgi to the vacuole and degraded. Because only the mutant protein is quantitatively proteolyzed these data suggest that a post-ER quality control check-point diverts unstable proteins to the vacuole for degradation. 相似文献
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Cochran JC Sontag CA Maliga Z Kapoor TM Correia JJ Gilbert SP 《The Journal of biological chemistry》2004,279(37):38861-38870
Eg5 is a slow, plus-end-directed microtubule-based motor of the BimC kinesin family that is essential for bipolar spindle formation during eukaryotic cell division. We have analyzed two human Eg5/KSP motors, Eg5-367 and Eg5-437, and both are monomeric based on results from sedimentation velocity and sedimentation equilibrium centrifugation as well as analytical gel filtration. The steady-state parameters were: for Eg5-367: k(cat) = 5.5 s(-1), K(1/2,Mt) = 0.7 microm, and K(m,ATP) = 25 microm; and for Eg5-437: k(cat) = 2.9 s(-1), K(1/2,Mt) = 4.5 microm, and K(m,ATP) = 19 microm. 2'(3')-O-(N-Methylanthraniloyl)-ATP (mantATP) binding was rapid at 2-3 microm(-1)s(-1), followed immediately by ATP hydrolysis at 15 s(-1). ATP-dependent Mt.Eg5 dissociation was relatively slow and rate-limiting at 8 s(-1) with mantADP release at 40 s(-1). Surprisingly, Eg5-367 binds microtubules more effectively (11 microm(-1)s(-1)) than Eg5-437 (0.7 microm(-1)s(-1)), consistent with the steady-state K(1/2,Mt) and the mantADP release K(1/2,Mt). These results indicate that the ATPase pathway for monomeric Eg5 is more similar to conventional kinesin than the spindle motors Ncd and Kar3, where ADP product release is rate-limiting for steady-state turnover. 相似文献
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The extracellular domain of epidermal growth factor receptor (EGFR-ECD) has been engineered through directed evolution and yeast surface display using conformationally-specific monoclonal antibodies (mAbs) as screening probes for proper folding and functional expression in Saccharomyces cerevisiae. An EGFR mutant with four amino acid changes exhibited binding to the conformationally-specific mAbs and human epidermal growth factor, and showed increased soluble secretion efficiency compared with wild-type EGFR. Full-length EGFR containing the mutant EGFR-ECD was functional, as assayed by EGF-dependent autophosphorylation and intracellular MAPK signaling in mammalian cells, and was expressed and localized at the plasma membrane in yeast. This approach should enable engineering of other complex mammalian receptor glycoproteins in yeast for genetic, structural, and biophysical studies. 相似文献
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Activated leukocyte cell adhesion molecule is a component of the endothelial junction involved in transendothelial monocyte migration 总被引:1,自引:0,他引:1
Masedunskas A King JA Tan F Cochran R Stevens T Sviridov D Ofori-Acquah SF 《FEBS letters》2006,580(11):2637-2645
Transendothelial leukocyte migration is a major aspect of the innate immune response. It is essential in repair and regeneration of damaged tissues and is regulated by multiple cell adhesion molecules (CAMs) including members of the immunoglobulin (Ig) superfamily. Activated leukocyte cell adhesion molecule (ALCAM/CD166) is an Ig CAM expressed by activated monocytes and endothelial cells. Hitherto, the functional relevance of ALCAM expression by endothelial cells and activated monocytes remained unknown. In this report, we demonstrate soluble recombinant human ALCAM significantly inhibited the rate of transendothelial migration of monocyte cell lines. Direct involvement of ALCAM in transendothelial migration was evident from the robust inhibition of this process by ALCAM blocking antibodies. However, soluble recombinant ALCAM had no impact on monocyte migration or adhesion to endothelium. Localization of ALCAM specifically at cell-cell junctions in endothelial cells supported its role in transendothelial migration. This study is the first to localize ALCAM to endothelial cell junctions and demonstrate a functional relevance for co-expression of ALCAM by activated monocytes and endothelial cells. 相似文献
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Parasitic Attachments by Overwintering Silver Lampreys, Ichthyomyzon unicuspis, and Chestnut Lampreys, Ichthyomyzon castaneus 总被引:1,自引:0,他引:1
We present evidence that at least some parasitic-phase silver lampreys, Ichthyomyzon unicuspis, and chestnut lampreys, I. castaneus, remain attached to host fish during the winter. Lake sturgeon, Acipenser fulvescens, harvested through the ice by spearfishers in the Lake Winnebago system in Wisconsin may bear silver lampreys or fresh lamprey wounds, and sturgeon with lamprey marks were significantly larger than sturgeon without them. Silver lampreys collected on paddlefish, Polyodon spathula, in the Wisconsin River in March were not significantly longer than silver lampreys collected previously in late October, but they were significantly heavier, an indication that they were feeding to at least some extent during the intervening period. Other large fish species, including northern pike, Esox lucius, and flathead catfish, Pylodictus olivaris, have been collected or observed during the winter with silver or chestnut lampreys attached. Although energy and nutrient intake by parasitic lampreys may be reduced during the winter, lampreys attached to hosts may also benefit from the hosts' mobility and ability to avoid potentially harmful situations. 相似文献