Functions of the HNK-1 antigen in the Nervous system and animal lectins in host defence system.

点击翻译按钮获取中文摘要

Studies on the roles of glycans in the nervous and host defence Systems.1. The role of HNK-1 antigen (SO_3-G1cA-LacNAc) in nervous system: Two glucuronyltransferase (G1cAT-P and G1cAT-S) genes associated with the biosynthesis of the HNK-lepitope were cloned and their gene-deficient mice were successfully generated. The G1cAT-P gene deficient mice lost the HNK-1 antigen in the brain almost completely. These mice exhibited reduced Long-term potentiation at the Schaffer collateral-CA1 synapses and a defect in spatial memory formation in the Morris water maize test. This is the first evidence that the loss of a single non-reducing terminal carbohydrate residue attenuates brain higher functions. We found that catalytic domains of G1cAT-P and G1cAT-S formed functional complexes with a sulfotransferase (HNK-1 ST) in the Golgi apparatus and facilitated the sequential biosynthesis of the complete HNK-1 antigen. Furthermore, we determined the x-ray crystal structures of human G1cAT-P and G1cAT-S … More and explain the reasons why these enzymes express their enzymic activity only in their homodimeric forms.2. Identification of endogenous ligands to mannan-binding protein, MBP: We previously noticed that the human MBP gene was shown to exhibit potent growth inhibitory activity toward human colorectal carcinoma, SW 1116 cells in nude mice via MBP-dependent cell-mediated cytotoxicity (MDCC). We successfully isolated the endogenous ligand glycans from SW1116 cells and their structures were characterized out in collaboration with Dr. Kay-Hooi Khoo in Academia Sinica. They were shown to be as large, multiantennary N-glycans carrying a highly fucosylated polylactosamine type structure and interestingly, at the nonreducing termini, Le^b/Le^a or tandem repeats of the Le^a structure prevail. These structures are unique and distinct from those of the previously reported tumor specific carbohydrate antigens. We also demonstrate that MBP binds specifically metalloproteases meprin α and β, which are highly expressed in kidney and small intestinal epithelial cells, leukocytes and certain cancer cells. Interestingly, MBP was found to inhibited the protease activity and matrix-degrading activity of meprins, suggesting the possibility that MBP may contribute as a potential therapeutic target to tumor progression. Less