The oligosaccharides on soluble and membrane glycoproteins exhibit tremendous structural diversity, suggesting they encode highly specific information. For this to be the case there must exist: l) Unique oligosaccharide structures, 2) Highly specific glycosyltransferases, and 3) Receptors capable of recognizing these structures and utilizing their unique information. Biologic functions making use of information encoded in oligosaccharides are likely to be manifest primarily in multicellular organisms and include such phenomena as cell:cell recognition, cell:matrix recognition, and both intra- and extra-cellular trafficking of glycoproteins. The challenge has been to identify systems which utilize the structural information encoded in oligosaccharides for a biologic purpose. We have identified a major new carbohydrate-specific receptor system in liver which regulates the circulatory half life and, thereby, the biologic activity of the glycoprotein hormone lutropin and other glycoproteins bearing terminal SO4-4GalNAc-beta, 14GlcNAc-beta1, 2Man- alpha (S4GGnM) on their oligosaccharides. The synthesis of S4GGnM-terminal structures is highly regulated and they are found on only a limited number of glycoproteins. Hepatic endothelial cell express >500,000 S4GGnM-binding sites/cell at their surface. The S4OGnM-receptor has been isolated from rat liver and will be extensively characterized using approaches we have developed for other carbohydrate-specific systems. The properties of the receptor will be defined in isolated hepatic endothelial cells. The primary structure will be determined by cDNA analysis. Proteolytic fragmentation and mutagenesis will be used to define the regions involved in ligand binding and targeting. Additional potential functions will be established by using the receptor to identify other glycoproteins bearing S4GGnM-terminal structures. Cells expressing the receptor in other tissues will be identified and characterized to establish if the receptor is part of a multigene family. Immunolocalization and in situ hybridization will be used to examine the regulation of S4GGnM-receptor expression during fetal development, pregnancy, and gain of sexual maturity in newborn rats. Since many glycoproteins including membrane glycoproteins on normal and malignant cells, surface glycoproteins on viruses, growth factor precursors, coagulation factors, complement components, and hormones may interact with the receptor system it has tremendous potential relevance to both pathologic and normal states.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA021923-18
Application #
2086985
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1977-08-01
Project End
1999-01-31
Budget Start
1995-02-06
Budget End
1996-01-31
Support Year
18
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mi, Yiling; Coonce, Marcy; Fiete, Dorothy et al. (2016) Functional Consequences of Mannose and Asialoglycoprotein Receptor Ablation. J Biol Chem 291:18700-17
Mi, Yiling; Lin, Angela; Fiete, Dorothy et al. (2014) Modulation of mannose and asialoglycoprotein receptor expression determines glycoprotein hormone half-life at critical points in the reproductive cycle. J Biol Chem 289:12157-67
Fiete, Dorothy; Beranek, Mary; Baenziger, Jacques U (2012) Molecular basis for protein-specific transfer of N-acetylgalactosamine to N-linked glycans by the glycosyltransferases ?1,4-N-acetylgalactosaminyl transferase 3 (?4GalNAc-T3) and ?4GalNAc-T4. J Biol Chem 287:29194-203
Baenziger, Jacques U (2012) Moving the O-glycoproteome from form to function. Proc Natl Acad Sci U S A 109:9672-3
Fiete, Dorothy; Beranek, Mary; Baenziger, Jacques U (2012) Peptide-specific transfer of N-acetylgalactosamine to O-linked glycans by the glycosyltransferases ?1,4-N-acetylgalactosaminyl transferase 3 (?4GalNAc-T3) and ?4GalNAc-T4. J Biol Chem 287:29204-12
Steirer, Lindsay M; Park, Eric I; Townsend, R Reid et al. (2009) The asialoglycoprotein receptor regulates levels of plasma glycoproteins terminating with sialic acid alpha2,6-galactose. J Biol Chem 284:3777-83
Fiete, D J; Beranek, M C; Baenziger, J U (1998) A cysteine-rich domain of the ""mannose"" receptor mediates GalNAc-4-SO4 binding. Proc Natl Acad Sci U S A 95:2089-93
Fiete, D; Beranek, M C; Baenziger, J U (1997) The macrophage/endothelial cell mannose receptor cDNA encodes a protein that binds oligosaccharides terminating with SO4-4-GalNAcbeta1,4GlcNAcbeta or Man at independent sites. Proc Natl Acad Sci U S A 94:11256-61
Fiete, D; Baenziger, J U (1997) Isolation of the SO4-4-GalNAcbeta1,4GlcNAcbeta1,2Manalpha-specific receptor from rat liver. J Biol Chem 272:14629-37
Manzella, S M; Hooper, L V; Baenziger, J U (1996) Oligosaccharides containing beta 1,4-linked N-acetylgalactosamine, a paradigm for protein-specific glycosylation. J Biol Chem 271:12117-20

Showing the most recent 10 out of 22 publications