The sulfogalactose moiety of sulfoglycosphingolipids serves as a mimic of tyrosine phosphate in many recognition processes. Prediction and demonstration of Src homology 2 domain/sulfogalactose binding.
Multiple ligand co-recognition of 3'-sulfogalactosylceramide (SGC) and sulfotyrosine initiated the comparison of SGC and sulfotyrosine and, subsequently, phosphotyrosine (pY) binding. SGC is a receptor for ligands involved in cell adhesion/microbial pathology. pY forms a Src homology domain 2 recognition motif in intracellular signaling. Using hsp70, anti-SGC, and anti-pY antibodies, ligand binding is retained following phosphate/sulfate and tyrosine/galactose substitution in SGC and sulfate/phosphate exchange in pY. Remarkable lipid-dependent binding to phosphatidylethanolamine-conjugated sulfotyrosine suggests "microenvironmental" modulation of sulfotyrosine-containing receptors, similar to glycosphingolipids. Based on an aryl substrate-bound co-crystal of arylsulfatase A, a sulfogalactose and phosphotyrosine esterase, modeling provides a solvation basis for co-recognition. c-Src/Src homology domain 2:SGC/phosphogalactosylceramide binding confirms our hypothesis, heralding a carbohydrate-based approach to regulation of phosphotyrosine-mediated recognition.
Lingwood
Clifford
C
Research Institute, The Hospital for Sick Children, Toronto, Ontario M4G 1X8, Canada. cling@sickkids.ca
Mylvaganam
Murugesapillai
M
Minhas
Farah
F
Binnington
Beth
B
Branch
Donald R
DR
Pomès
Régis
R
D020816:Amino Acid Motifs; D001665:Binding Sites; D002236:Carbohydrate Conformation; D002448:Cell Adhesion; D002553:Cerebroside-Sulfatase / Q000737:chemistry; D002855:Chromatography, Thin Layer; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D018076:DNA, Complementary / Q000378:metabolism; D005690:Galactose / Q000737:chemistry* / Q000378:metabolism; D006028:Glycosphingolipids / Q000737:chemistry*; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D010710:Phosphates / Q000737:chemistry; D019000:Phosphotyrosine / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013431:Sulfates / Q000737:chemistry; D014443:Tyrosine / Q000737:chemistry; D018909:src Homology Domains
D018076:DNA, Complementary; D006028:Glycosphingolipids; D018840:HSP70 Heat-Shock Proteins; D008024:Ligands; D010710:Phosphates; D013431:Sulfates; D019000:Phosphotyrosine; D014443:Tyrosine; D002553:Cerebroside-Sulfatase; D005690:Galactose