Structure Based Substrate Specificity Analysis of Heparan Sulfate 6-O-Sulfotransferases

详细信息    查看全文

• 作者：Yongmei Xu ; Andrea F. Moon ; Shuqin Xu ; Juno M. Krahn ; Jian LiuLars C. Pedersen
• 刊名：ACS Chemical Biology
• 出版年：2017
• 出版时间：January 20, 2017
• 年：2017
• 卷：12
• 期：1
• 页码：73-82
• 全文大小：765K
• ISSN：1554-8937

文摘

Heparan sulfate (HS) is a sulfated polysaccharide exhibiting essential physiological functions. HS 6-O-sulfotransferase (6-OST) transfers a sulfo group to the 6-OH position of glucosamine units to confer a variety of HS biological activities. There are three different isoforms of 6-OST in the human genome. Here, we report crystal structures of the ternary complex of 6-OST with the sulfo donor analog 3′-phosphoadenosine 5′-phosphate and three different oligosaccharide substrates at 1.95 to 2.1 Å resolutions. Structural and mutational analyses reveal amino acid residues that contribute to catalysis and substrate recognition of 6-OST. Unexpectedly, the structures reveal 6-OST engages HS in a completely different orientation than other HS sulfotransferases and sheds light on the basic HS requirements for specificity. These findings also contribute structural information to understand mutations in human 6-OST isoform 1 associated with the human genetic disease idiopathic hypogonadotropic hypogonadism characterized by incomplete or lack of puberty.