Crystal Structure of an α1,4-N-Acetylhexosaminyltransferase (EXTL2), a Member of the Exostosin Gene Family Involved in Heparan Sulfate Biosynthesis*

By Lars C. Pedersen, Jian Dong, F. Taniguchi, H. Kitagawa, J. Krahn, L. G. Pedersen, K. Sugahara, M. Negishi. 2003

113 citations recorded by the source corpus.

EXTL2, an α1,4-N-acetylhexosaminyltransferase, catalyzes the transfer reaction of N-acetylglucosamine andN-acetylgalactosamine from the respective UDP-sugars to the non-reducing end of [glucuronic acid]β1–3[galactose]β1-O-naphthalenemethanol, an acceptor substrate analog of the natural common linker of various glycosylaminoglycans. We have solved the x-ray crystal structure of the catalytic domain of mouse EXTL2 in the apo-form and with donor substrates UDP-N-acetylglucosamine and UDP-N-acetylgalactosamine. In addition, a structure of the ternary complex with UDP and the acceptor substrate analog [glucuronic acid]β1–3[galactose]β1-O-naphthalenemethanol has been determined. These structures reveal three highly conserved residues, Asn-243, Asp-246, and Arg-293, located at the active site. Mutation of these residues greatly decreases the activity. In the ternary complex, an interaction exists between the β-phosphate of the UDP leaving group and the acceptor hydroxyl of the substrate that may play a functional role in catalysis. These structures represent the first structures from the exostosin gene family and provide important insight into the mechanisms of α1,4-N-acetylhexosaminyl transfer in heparan biosynthesis.

Subfields: Cell Biology, Molecular Biology

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In Molecular Biology

1. Bernard Henrissat
2. Pedro M. Coutinho
3. R. Wanders

Citations in the corpus

• An evolving hierarchical family classification for glycosyltransferases. (2003, background): “The second module, GT64, found in isolation in other plants genes, is an a-N-acetylglucosaminidase.(40) These observations demand systematic analyses of the modular structure of glycosyltransferases.”
• The exostosin family: proteins with many functions. (2014, unknown): “In fact, recombinant EXTL2 was found to transfer α-linked GalNAc much more efficiently than α-linked GlcNAc to the synthetic linkage-region analog (Kitagawa et al., 1999; Pedersen et al., 2003) that may suggest a function for this enzyme other than as an initiator of HS biosynthesis.”
• Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome. (2017, background): “In addition, there are two predicted Pfam domains: a conserved EXT domain (amino acids 190–500) and a glycosyl transferase family 64 domain (amino acids 663–904) conserved between enzymes that catalyze the transfer reaction of N-acetylglucosamine and N-acetylgalactosamine.(44) Please cite this artic”