Misfolded glycoproteins are translocated from the endoplasmic reticulum (ER) into the cytoplasm for proteasome-mediated degradation. OS-9 protein is thought to participate in ER-associated glycoprotein degradation (ERAD). The recombinant biotinylated mannose 6-phosphate receptor homology (MRH) domain of human OS-9 (OS-9(MRH)) together with six kinds of mutated OS-9(MRH) were prepared and mixed with R-phycoerythrin (PE)-labeled streptavidin to form tetramers (OS-9(MRH)-SA). The PE-labeled OS-9(MRH)-SA bound to HeLaS3 cells in a metal ion-independent manner through amino acid residues homologous to those participating in sugar binding of the cation-dependent mannose 6-phosphate receptor, and this binding was greatly increased by swainsonine, deoxymannojirimycin, or kifunensine treatment. N-Acetylglucosaminyltransferase I-deficient Lec1 cells, but not Lec2 or Lec8 cells, were also strongly bound by the tetramer. OS-9(MRH)-SA binding to the cells was strongly inhibited by Manalpha1,6(Manalpha1,3)Manalpha1,6(Manalpha1,3)Man and Manalpha1,6Man. To further determine the specificity of native ligands for OS-9(MRH), frontal affinity chromatography was performed using a wide variety of 92 different oligosaccharides. We found that several N-glycans containing terminal alpha1,6-linked mannose in the Manalpha1,6(Manalpha1,3)Manalpha1,6(Manalpha1,3)Man structure were good ligands for OS-9(MRH), having K(a) values of approximately 10(4) M(-1) and that trimming of either an alpha1,6-linked mannose from the C-arm or an alpha1,3-linked mannose from the B-arm abrogated binding to OS-9(MRH). An immunoprecipitation experiment demonstrated that the alpha1-antitrypsin variant null(Hong Kong), but not wild-type alpha1-antitrypsin, selectively interacted with OS-9 in the cells in a sugar-dependent manner. These results suggest that trimming of the outermost alpha1,2-linked mannose on the C-arm is a critical process for misfolded proteins to enter ERAD.
Background: Malectin may play a role in the quality control of glycoproteins, but the underlying molecular mechanism(s) is not known. Results: Malectin forms a complex with ribophorin I for enhanced association with misfolded glycoproteins. Conclusion: Malectin functions by forming a complex with ribophorin I. Significance: This might be the first evidence for the preferential association of malectin with misfolded glycoproteins.
Background:The mechanism of HCC resistant to Fas-mediated apoptosis is not clearly understood. Results: ORP8 triggered HCC cell apoptosis via relocation of cytoplasmic Fas to the cell plasma membrane and FasL up-regulation. Conclusion: ORP8 increases sensitivity of HCC cells to Fas-mediated apoptosis. Significance: New insights reveal that ORP8 may serve as a potential target for HCC therapy.
In cells, human malectin stably interacted with newly synthesized ATNHK, but not AT, via G2M9 glycans. The interaction of ATNHK with malectin resulted in enhanced ERAD of ATNHK and prevented the secretion of the misfolded glycoprotein. These findings provide evidence of a role of malectin in glycoprotein quality control via recognition of G2M9.
Dimericbiscognienyne A (1), an unusual diisoprenyl-cyclohexene-type meroterpenoid dimer, was isolated from Biscogniauxia sp. together with three new monomeric diisoprenyl-cyclohexene-type meroterpenoids (2-4) and one new isoprenyl-benzoic acid-type meroterpenoid (5). All structures were determined by extensive NMR spectroscopic methods, quantum chemical calculations, chemical derivatization, and X-ray crystallography. The formation of 1 is related to a unique intermolecular redox coupling Diels-Alder adduct reaction. Their cytotoxicities and short-term memory enhancement activities against Alzheimer's disease were assessed.
Furanosteroids, represented by wortmannin, viridin, and demethoxyviridin, are a special group of fungal-derived, highly oxygenated steroids featured by an extra furan ring. They are well-known nanomolar-potency inhibitors of phosphatidylinositol 3-kinase and widely used in biological studies. Despite their importance, the biosyntheses of these molecules are poorly understood. Here, we report the identification of the biosynthetic gene cluster for demethoxyviridin, consisting of 19 genes, and among them 15 biosynthetic genes, including six cytochrome P450 monooxygenase genes, are deleted. As a result, 14 biosynthetic intermediates are isolated, and the biosynthetic pathway for demethoxyviridin is elucidated. Notably, the pregnane side-chain cleavage requires three enzymes: flavin-dependent Baeyer-Villiger monooxygenase, esterase, and dehydrogenase, in sharp contrast to the single cytochrome P450-mediated process in mammalian cells. Structure–activity analyses of these obtained biosynthetic intermediates reveal that the 3-keto group, the C1β–OH, and the aromatic ring C are important for the inhibition of phosphatidylinositol 3-kinase.
Fusarins G1/G2 (1/2) and G3/G4 (3/4), two sets of interesting examples of diastereoisomers with substantially identical NMR data, were discovered from natural products. The reason was discussed and the generally applicable determinant conditions were proposed. The minimum interval for stereoclusters to be entirely segregated was also discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.