Abstract
SummaryProteoglycans (PGs) are essential components of the animal extracellular matrix and are required for cell adhesion, migration, signaling, and immune function. PGs are composed of a core protein and long glycosaminoglycan (GAG) chains, which often specify PG function. GAG biosynthesis is initiated by peptide O-xylosyltransferases, which transfer xylose onto selected serine residues in the core proteins. We have determined crystal structures of human xylosyltransferase 1 (XT1) in complex with the sugar donor, UDP-xylose, and various acceptor peptides. The structures reveal unique active-site features that, in conjunction with functional experiments, explain the substrate specificity of XT1. A constriction within the peptide binding cleft requires the acceptor serine to be followed by glycine or alanine. The remainder of the cleft can accommodate a wide variety of sequences, but with a general preference for acidic residues. These findings provide a framework for understanding the selectivity of GAG attachment.
Highlights
Proteoglycans (PGs) are a diverse family of glycoproteins characterized by the presence of one or more covalently attached glycosaminoglycan (GAG) chains, which often dominate the biophysical properties and biological functions of PGs
GAGs are polymers of repeating disaccharide units consisting of a hexosamine and a uronic acid sugar; the polymer is modified by sulfation at various positions (Esko et al, 2009; Iozzo and Schaefer, 2015)
GAGs are classified as either heparan sulfate (HS) or as chondroitin sulfate (CS) and dermatan sulfate (DS)
Summary
Proteoglycans (PGs) are a diverse family of glycoproteins characterized by the presence of one or more covalently attached glycosaminoglycan (GAG) chains, which often dominate the biophysical properties and biological functions of PGs. GAGs are polymers of repeating disaccharide units consisting of a hexosamine and a uronic acid sugar; the polymer is modified by sulfation at various positions (Esko et al, 2009; Iozzo and Schaefer, 2015). GAGs are classified as either heparan sulfate (HS) or as chondroitin sulfate (CS) and dermatan sulfate (DS). PGs are present on the cell surface and in the extracellular matrix of all higher animals They are essential components of extracellular matrices and play important roles in cell adhesion and migration, morphogen and growth factor signaling, immune regulation, and the inflammatory response. PG dysfunction is linked to many conditions with major public health implications, such as arthritis, diabetes, neurodegenerative diseases, atherosclerosis, and cancer (Bishop et al, 2007; Couchman, 2010; Mikami and Kitagawa, 2013)
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