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The structure of human α-2,6-sialyltransferase reveals the binding mode of complex glycans.

Kuhn B, Benz J, Greif M, Engel AM, Sobek H, Rudolph MG
Acta Crystallogr D Biol Crystallogr 69 1826-38 (2013)
Cited: 53 times
EuropePMC logo PMID: 23999306

Abstract

Human β-galactoside α-2,6-sialyltransferase I (ST6Gal-I) establishes the final glycosylation pattern of many glycoproteins by transferring a sialyl moiety to a terminal galactose. Complete sialylation of therapeutic immunoglobulins is essential for their anti-inflammatory activity and protein stability, but is difficult to achieve in vitro owing to the limited activity of ST6Gal-I towards some galactose acceptors. No structural information on ST6Gal-I that could help to improve the enzymatic properties of ST6Gal-I for biotechnological purposes is currently available. Here, the crystal structures of human ST6Gal-I in complex with the product cytidine 5'-monophosphate and in complex with cytidine and phosphate are described. These complexes allow the rationalization of the inhibitory activity of cytosine-based nucleotides. ST6Gal-I adopts a variant of the canonical glycosyltransferase A fold and differs from related sialyltransferases by several large insertions and deletions that determine its regiospecificity and substrate specificity. A large glycan from a symmetry mate localizes to the active site of ST6Gal-I in an orientation compatible with catalysis. The glycan binding mode can be generalized to any glycoprotein that is a substrate of ST6Gal-I. Comparison with a bacterial sialyltransferase in complex with a modified sialyl donor lends insight into the Michaelis complex. The results support an SN2 mechanism with inversion of configuration at the sialyl residue and suggest substrate-assisted catalysis with a charge-relay mechanism that bears a conceptual similarity to serine proteases.

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  6. Probing the CMP-Sialic Acid Donor Specificity of Two Human β-d-Galactoside Sialyltransferases (ST3Gal I and ST6Gal I) Selectively Acting on O- and N-Glycosylproteins. Noel M, Gilormini PA, Cogez V, Yamakawa N, Vicogne D, Lion C, Biot C, Guérardel Y, Harduin-Lepers A. Chembiochem 18 1251-1259 (2017)
  7. The Human Lung Glycome Reveals Novel Glycan Ligands for Influenza A Virus. Jia N, Byrd-Leotis L, Matsumoto Y, Gao C, Wein AN, Lobby JL, Kohlmeier JE, Steinhauer DA, Cummings RD. Sci Rep 10 5320 (2020)
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  14. Potent Metabolic Sialylation Inhibitors Based on C-5-Modified Fluorinated Sialic Acids. Heise T, Pijnenborg JFA, Büll C, van Hilten N, Kers-Rebel ED, Balneger N, Elferink H, Adema GJ, Boltje TJ. J. Med. Chem. 62 1014-1021 (2019)
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  19. A universal glycoenzyme biosynthesis pipeline that enables efficient cell-free remodeling of glycans. Jaroentomeechai T, Kwon YH, Liu Y, Young O, Bhawal R, Wilson JD, Li M, Chapla DG, Moremen KW, Jewett MC, Mizrachi D, DeLisa MP. Nat Commun 13 6325 (2022)
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  22. Intradomain Interactions in an NMDA Receptor Fragment Mediate N-Glycan Processing and Conformational Sampling. Subedi GP, Sinitskiy AV, Roberts JT, Patel KR, Pande VS, Barb AW. Structure 27 55-65.e3 (2019)
  23. Structural and functional role of disulphide bonds and substrate binding residues of the human beta-galactoside alpha-2,3-sialyltransferase 1 (hST3Gal1). Ortiz-Soto ME, Reising S, Schlosser A, Seibel J. Sci Rep 9 17993 (2019)
  24. The Rapidly Expanding Nexus of Immunoglobulin G N-Glycomics, Suboptimal Health Status, and Precision Medicine. Russell A, Wang W. Exp Suppl 112 545-564 (2021)
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