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Hudgin et al. 249 (17): 5536
Kawasaki and Ashwell 252 (18): 6536
J. Biol. Chem., Vol. 281, Issue 43, 34, October 27, 2006
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Classics
Hepatic Carbohydrate Binding Proteins and Glycoprotein Catabolism: the Work of Gilbert G. Ashwell
The Isolation and Properties of a Rabbit Liver Binding Protein Specific for Asialoglycoproteins
(Hudgin, R. L., Pricer, W. E., Jr., Ashwell, G., Stockert, R. J., and Morell, A. G. (1974) J. Biol. Chem. 249, 5536–5543)
Isolation and Characterization of an Avian Hepatic Binding Protein Specific for N-Acetylglucosamine-terminated Glycoproteins
(Kawasaki, T., and Ashwell, G. (1977) J. Biol. Chem. 252, 6536–6543)
G. Gilbert Ashwell was born in Jersey City, New Jersey, in 1916. He attended the University of Illinois where he earned his B.A. in 1938 and his M.S. in 1941. Ashwell then went to Columbia University and received his M.D. in 1948. After graduating, he remained at Columbia University as a research fellow for 2 years. In 1950, Ashwell joined the National Institute of Arthritis, Metabolism, and Digestive Diseases at the National Institutes of Health. The Institute later split into the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases, where Ashwell remains today as emeritus scientist.
Ashwell is perhaps best known for his work with Anatol G. Morell in which they proposed that membrane lectins remove senescent circulating glycoproteins and discovered one of the earliest known carbohydrate receptors. Ashwell met Morell when he was on sabbatical leave at Columbia University in 1965. Morell, who was at the Albert Einstein College of Medicine in the Bronx, was interested in devising a method for labeling serum glycoproteins to study the role of ceruloplasmin in Wilson disease. Together, Ashwell and Morell devised a labeling procedure (1) that involved enzymatic removal of the glycoprotein's terminal sialic acid residue, thereby exposing galactose which was then treated with galactose oxidase and tritiated borohydride, resulting in the incorporation of tritium into the protein.
When they injected their radioactive ceruloplasmin into rabbits, Ashwell and Morell noticed that the asialoglycoproteins rapidly disappeared from the serum and appeared in parenchymal cells in the liver (2). Further investigations showed that this phenomenon occurred with a variety of naturally occurring plasma glycoproteins (3) and that the plasma membranes of the liver were the primary site of binding for the circulating glycoproteins (4). This led to the hypothesis that the exposure of terminal, nonreducing galactosyl residues by the removal of sialic acid provides a means by which the liver recognizes and removes the defective molecules from circulation as part of their normal catabolic pathway.
As described in the first Journal of Biological Chemistry (JBC) Classic reprinted here, Ashwell and Morell eventually isolated the asialoglycoprotein binding protein from rabbit liver using an affinity column composed of asialoorosomucoid covalently linked to Sepharose 4B.
Several years later, Ashwell and Toshisuke Kawasaki isolated an avian hepatic binding protein that was specific for terminal N-acetylglucosamine residues on glycoproteins. This is the subject of the second JBC Classic reprinted here. They compared the avian and rabbit proteins and found that they had many properties in common, such as similar carbohydrate constituents and a requirement for calcium. However, the two proteins also differed in many ways. For example, the avian protein, in contrast to the mammalian protein, exhibited only minimal binding activity for asialoglycoproteins but interacted strongly with agalactoglycoproteins. The structures of the two proteins also differed. The rabbit protein consisted of two different subunits that were 48,000 and 40,000 daltons. The avian protein contained a single subunit with an estimated molecular weight of 26,000.
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Ashwell's work on hepatic binding proteins has served as a stimulus for the identification of a host of carbohydrate-specific receptors on various cell surfaces and has inaugurated the current concept of a "cellular lectin." In recognition of his contributions to science, Ashwell has received many awards including the Gairdner Foundation International Award in 1982, the Merck Prize from the American Society for Biological Chemists (now the American Society for Biochemistry and Molecular Biology) in 1984, and the Senior Scientist Award from the Alexander von Humboldt Foundation in 1989. He was elected to the National Academy of Sciences in 1979.
REFERENCES
- Morell, A. G., Van Den Hamer, C. J. A., Scheinberg, I. H., and Ashwell, G. (1966) Physical and chemical studies on ceruloplasmin. IV. Preparation of radioactive, sialic acid-free ceruloplasmin labeled with tritium on terminal D-galactose residues. J. Biol. Chem. 241, 3745–3749
[Abstract/Free Full Text] - Morell, A. G., Irvine, R. A., Sternlieb, I., Scheinberg, I. H., and Ashwell, G. (1968) Physical and chemical studies on ceruloplasmin. V. Metabolic studies on sialic acid-free ceruloplasmin in vivo. J. Biol. Chem. 243, 155–159
[Abstract/Free Full Text] - Morell, A. G., Gregoriadis, G., Scheinberg, I. H., Hickman, J., and Ashwell, G. (1971) The role of sialic acid in determining the survival of glycoproteins in the circulation. J. Biol. Chem. 246, 1461–1467
[Abstract/Free Full Text] - Pricer, W. E., and Ashwell, G. (1971) The binding of desialylated glycoproteins by plasma membranes of rat liver. J. Biol. Chem. 246, 4825–4833
[Abstract/Free Full Text]
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