1. Structure Based Substrate Specificity Analysis of Heparan Sulfate 6-O-Sulfotransferases
- Author
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Yongmei Xu, Jian Liu, Juno M. Krahn, Andrea F. Moon, Lars C. Pedersen, and Shuqin Xu
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Stereochemistry ,Oligosaccharides ,Sequence alignment ,Crystallography, X-Ray ,Biochemistry ,Article ,Substrate Specificity ,03 medical and health sciences ,chemistry.chemical_compound ,Sulfation ,Protein structure ,Glucosamine ,Catalytic Domain ,Animals ,Humans ,Protein Isoforms ,Transferase ,Amino Acid Sequence ,Ternary complex ,Peptide sequence ,Zebrafish ,030102 biochemistry & molecular biology ,fungi ,General Medicine ,Heparan sulfate ,Zebrafish Proteins ,Adenosine Diphosphate ,030104 developmental biology ,chemistry ,Molecular Medicine ,Sulfotransferases ,Sequence Alignment - Abstract
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.
- Published
- 2016