Human serum amyloid P is a multispecific adhesive protein whose ligands include 6-phosphorylated mannose and the 3-sulphated saccharides galactose, N-acetylgalactosamine and glucuronic acid.
Carbohydrate recognition by amyloid P component from human serum has been investigated by binding experiments using several glycosaminoglycans, polysaccharides and a series of structurally defined neoglycolipids and natural glycolipids. Two novel classes of carbohydrate ligands have been identified. The first is 6-phosphorylated mannose as found on lysosomal hydrolases, and the second is the 3-sulphated saccharides galactose, N-acetyl-galactosamine and glucuronic acid as found on sulphatide and other acidic glycolipids that occur in neural or kidney tissues or on subpopulations of lymphocytes. Binding to mannose-6-phosphate containing molecules and inhibition of binding by free mannose-6-phosphate and fructose-1-phosphate are features shared with mannose-6-phosphate receptors involved in trafficking of lysosomal enzymes. However, only amyloid P binding is inhibited by galactose-6-phosphate, mannose-1-phosphate and glucose-6-phosphate. These findings strengthen the possibility that amyloid P protein has a central role in amyloidogenic processes: first in formation of focal concentrations of lysosomal enzymes including proteases that generate fibril-forming peptides from amyloidogenic proteins, and second in formation of multicomponent complexes that include sulphoglycolipids as well as glycosaminoglycans. The evidence that binding to all of the acidic ligands involves the same polypeptide domain on amyloid P protein, and inhibition data using diffusible, phosphorylated monosaccharides, is potentially important leads to novel drug designs aimed at preventing or even reversing amyloid deposition processes without interference with essential lysosomal trafficking pathways.
Loveless
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RW
Glycoconjugates Section, MRC Clinical Research Centre, Harrow, Middlesex, UK.
Floyd-O'Sullivan
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G
Raynes
J G
JG
Yuen
C T
CT
Feizi
T
T
D000116:Acetylgalactosamine / Q000378:metabolism*; D000595:Amino Acid Sequence; D002097:C-Reactive Protein / Q000378:metabolism; D002240:Carbohydrate Sequence; D002855:Chromatography, Thin Layer; D005690:Galactose / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism*; D020723:Glucuronic Acid; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008360:Mannosephosphates / Q000378:metabolism*; D008969:Molecular Sequence Data; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D013464:Sulfuric Acids / Q000378:metabolism
D005965:Glucuronates; D006017:Glycolipids; D008024:Ligands; D008360:Mannosephosphates; D000683:Serum Amyloid P-Component; D013464:Sulfuric Acids; D020723:Glucuronic Acid; D002097:C-Reactive Protein; D000116:Acetylgalactosamine; D005690:Galactose