Heparan sulfate 3-O-sulfation: A rare modification in search of a function

Abstract

Many protein ligands bind to heparan sulfate, which results in their presentation, protection, oligomerization or conformational activation. Binding depends on the pattern of sulfation and arrangement of uronic acid epimers along the chains. Sulfation at the C3 position of glucosamine is a relatively rare, yet biologically significant modification, initially described as a key determinant for binding and activation of antithrombin and later for infection by Type I Herpes Simplex virus. In mammals, a family of seven heparan sulfate 3-O-sulfotransferases installs sulfate groups at this position and constitutes the largest group of sulfotransferases involved in heparan sulfate formation. However, to date very few proteins or biological systems have been described that are influenced by 3-O-sulfation. This review describes our current understanding of the prevalence and structure of 3-O-sulfation sites, expression and substrate specificity of the 3-O-sulfotransferase family and the emerging roles of 3-O-sulfation in biology.

Pharmacology of Heparin and Related Drugs

“…A high-resolution crystal structure of 3-OST-1 with a synthetic heptasaccharide (Moon et al, 2012) provided detailed insights on the induced oligosaccharide conformations on initial binding to this enzyme, and comparisons with the earlier structure of 3-OST-3 (Moon et al, 2004) allow insight into the structural selectivity of 3-OST isoforms. 3-OSTs can be divided into two groups: the AT-binding group, 3-OST-1 and 3-OST-5, which require GlcA before the modified GlcN; and the glycoprotein D (gD) group, 3-OST-2, 3-OST-3, 3-OST-4, and 3-OST-6, which require IdoA2S in that position (Thacker et al, 2014). Of these, the evidence that DNA hypermethylation of 3-OST genes is associated with several common cancers is of particular interest (Miyamoto et al, 2003;Shivapurkar et al, 2007).…”

The heparan sulfate sulfotransferase 3-OST3A (HS3ST3A) is a novel tumor regulator and a prognostic marker in breast cancer

“…11,15,31 Our study shows that 3-OST3A was repressed and subjected to hypermethylation in all breast cancer cell lines tested except in HER2+-SKBR3 cells in which, consistently, it was expressed at relatively high level. Further analysis of the chromatin interactors at the 3-OST3A promoter showed that the epigenetic regulation not only depends upon DNA methylation, but also on repressive histone marks, and involves the recruitment of PcG proteins.…”

Heparan Sulfate Proteoglycans Mediate Factor XIIa Binding to the Cell Surface

“…For example, 6-O-sulfation of HS was found to regulate TGF-␤ signaling in fibroblasts and to promote the interaction of urokinase with u-PAR on the cell surface (46). In addition, 6-O-sulfation mediated the binding of the platelet-derived growth factor, hepatocyte growth factor, and lipoprotein lipase to the HS, whereas the binding of the epidermal growth factor, fibroblast growth factor (FGF)-2, and FGF receptor to HS was dependent on both 6-O-and 2-O-sulfation, and the interaction with antithrombin required the presence of 6-O-and 3-O-sulfate groups (47,48). Moreover, the expression of SULF1, an enzyme catalyzing the removal of 6-O-sulfate groups from HS, was found to be down-regulated in several cancer cell types, resulting in increased HS sulfation and subsequently enhanced epidermal growth factor signaling (41).…”