Abstract
Sialyltransferases of the mammalian ST8Sia family catalyze oligo- and polysialylation of surface-localized glycoproteins and glycolipids through transfer of sialic acids from CMP–sialic acid to the nonreducing ends of sialic acid acceptors. The crystal structure of human ST8SiaIII at 1.85-Å resolution presented here is, to our knowledge, the first solved structure of a polysialyltransferase from any species, and it reveals a cluster of polysialyltransferase-specific structural motifs that collectively provide an extended electropositive surface groove for binding of oligo–polysialic acid chain products. The ternary complex of ST8SiaIII with a donor sugar analog and a sulfated glycan acceptor identified with a sialyltransferase glycan array provides insight into the residues involved in substrate binding, specificity and sialyl transfer.
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Acknowledgements
We wish to acknowledge the Consortium for Functional Glycomics (grants GM62116 and GM098791) for the sialyltransferase glycan array and for biotinylated CMP–Neu5Ac and the Canadian Light Source and Advanced Light Source for access to synchrotron data collection facilities. We also acknowledge operating funds from the Canadian Institutes of Health Research (N.C.J.S., S.G.W., W.W. and L.J.F.), the Howard Hughes Medical Institute International Senior Scholar program (N.C.J.S.) and the Canadian Foundation of Innovation and British Columbia Knowledge Development Fund (N.C.J.S., S.G.W. and L.J.F.). N.C.J.S. and S.G.W. are supported as Tier 1 Canada Research Chairs. G.V. is supported by fellowships from the Michael Smith Foundation for Health Research and the Canadian Department for Foreign Affairs and International Trade. L.B. is supported by the Deutsche Forschungsgemeinschaft. A Cystic Fibrosis Canada Fellowship supports E.L. The Ministry of Science and Technology, Taiwan (NSC-103-2917-I-564-009) supports C.-C.Y.
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G.V. designed the constructs and performed expression, purification, crystallization, data collection and processing as well as solution and refinement of crystallographic structures. L.J.W. phased the initial native structure, assisted with refinement of various data sets and performed Rosetta docking and modeling with protein acceptors. E.L. performed size-exclusion chromatography with multiangle light scattering experiments. G.A.W. performed biolayer interferometry experiments. L.B. and C.-C.Y. synthesized donor analog and acceptor compounds, and D.H.K. performed kinetic experiments. N.E.S. and L.J.F. performed and analyzed LC-MS experiments. W.W. contributed to analysis of glycan-array data. G.V., L.J.W., S.G.W. and N.C.J.S. designed the structural, mechanistic and kinetic experiments, analyzed the resulting data and wrote the manuscript. We thank A. Seitova (Structural Genomics Consortium Toronto) for reagents.
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Supplementary Figure 1 Purification and thin-layer chromatography (TLC) assays of ST8SiaIII.
(a) Elution profile of ST8SiaIII Δ60 examined by SEC-MALS with Coomassie-stained SDS-PAGE in the right top corner showing the crude expression medium of human ST8SiaIII Δ60 (50x concentrated, A), elution of the IMAC Ni2+ affinity column (B), elution of the S200 size-exclusion column (C), EndoH Hf (D) and PNGaseF (E) digested ST8SiaIII Δ60 and pure, concentrated ST8SiaIII Δ60 (F) protein. (b) TLC assay of wild type ST8SiaIII and mutant His354Ala with BODIPY-diSiaLac as acceptor, 1) no enzyme 2) positive control, ST8SiaIV Δ60 3) wild type ST8SiaIII Δ60 4) ST8SiaIII Δ60 mutant His354Ala. (c) TLC assay of wild type ST8SiaIII and ST8SiaII with BODIPY-diSiaLac as acceptor, 1) no enzyme 2) positive control 3) wild type ST8SiaIII Δ60 4) ST8SiaII Δ85. (d) TLC assay of wild type ST8SiaIII and mutants Asn190Ala, His337Ala with BODIPY-diSiaLac as acceptor, 1) no enzyme 2) positive control, ST8SiaIV Δ60 3) wild type ST8SiaIII Δ60 4) ST8SiaIII Δ60 mutant Asn190Ala 5) ST8SiaIII Δ60 mutant His337Ala.
Supplementary Figure 2 Topology of human ST8SiaIII.
(a) Topology diagram of human ST8SiaIII created with PDBsum (https://www.ebi.ac.uk/pdbsum/). (b) Overlap of monomer A of human ST8SiaIII (green) with human ST6GalI24 (4JS2, blue) bound to CMP (blue, ball & stick representation) and porcine ST3GalI23 (2WML, magenta) based on a secondary structure match (r.m.s.d. of 2.6 Å over ~200 common Cα). Note the conserved core of the sialyltransferases including the seven-stranded β-sheet around the donor-binding site.
Supplementary Figure 3 Sequence alignment of human ST8SiaIII with human ST8SiaII and ST8SiaIV.
Motifs highlighted (polybasic region, blue; large, green; polysialyltransferase domain, cyan; small, orange; III, black; very small, violet) and predicted transmembrane helix shown in grey. The header shows the most prevalent residues in small letters and conserved residues in capitalized red letters. Black asterisks refer to glycosylation sites Asn93, 113, 160 and 206 of ST8SiaIII. The alignment was created with Clustal Omega (http://www.ebi.ac.uk/Tools/msa/clustalo/) and UCSF Chimera68.
Supplementary Figure 4 Ternary-complex electron density maps, alternate conformations and comparison with porcine ST3GalI.
(a) Simulated annealing omit map of monomer A of the ternary complex (calculated with PHENIX in absence of donor and acceptor at 2.3 Å resolution; 2mFo-DFc (blue) contoured at 1σ, mFo-DFc (green) at 3σ, acceptor Sia-6S-LacNAc orange, donor analogue CMP-3FNeu5Ac dark green with disordered atom positions indicated at 85% transparency, His354 magenta. (b) Omit electron density of monomer B of the ternary complex (coloring see a). (c) Refined electron density map of monomer A (2mFo-DFc blue at 1σ, mFo-DFc green at 3σ). (d) Refined electron density map of monomer B (coloring see a). (e) Close-up on the simulated annealing omit map of the donor in monomer A of the ternary complex (coloring as in a). (f) Close-up on the simulated annealing omit map of the donor CMP-3FNeu5Ac in monomer B of the ternary complex (coloring as in a). (g) Overlap of Sia-6S-LacNAc of monomer A (yellow) on Sia-6S-LacNAc of monomer B (orange, r.m.s.d. 0.8 Å on all atoms) of the ternary complex. Note the different conformations of the glycerol group (black circle), with Sia-6S-LacNAc of monomer B exhibiting the catalytically permissive conformation for the C8 hydroxyl group. (h) Composite view of ternary complex of ST8SiaIII with CMP-3FNeu5Ac (monomer A) and Sia-6S-LacNAc (Sia-6S-LacNAc of monomer B, r.m.s.d of 0.8 Å to all atoms of Sia-6S-LacNAc of monomer A). (i) ST3GalI bound to acceptor and CMP23 (blue, PDB 2WNB).
Supplementary Figure 5 ESI-MS analysis and kinetics assay control to test for donor hydrolysis.
ESI-MS analysis of (a) axial CMP-3FNeu5Ac alone and (b) after 4 day incubation with ST8SiaIII Δ80. Data were recorded in the negative mode with dilutions ranging one order of magnitude. (c) CMP release (coupled to NADH oxidation measured by absorbance at 340 nm) using the assay conditions as described in methods, both before (in unfilled squares) and after (in filled circles) addition of ST8SiaIII to 1 μM. CMP-SA concentration was fixed at 1 mM and SiaLacNAc-6S concentration was varied. At 0 SiaLacNAc-6S, when the enzyme is added, there is no difference in the rate compared to the background control measurements before the enzyme is added. The background rate likely arises from spontaneous oxidation of NADH.
Supplementary Figure 6 Representative poses from top-scoring RosettaDock clusters in addition to the top pose shown in Figure 4d.
NCAM FN1 domain colored according to energy plot on Figure 4c. Superposed NCAM Ig5 domain (not used in docking) colored grey and distances between modified glycans Asn449 and Asn478 to active site Lys297 shown (diamond; only labeled in top left panel). The ST8SiaIV PBR is colored blue and the PSTD cyan. Residues implicated in the interaction are shown as spheres (NCAM FN1 acidic patch marked with a circle, ST8SiaIV PBR Arg93 marked with star, PBR Arg82 with a diamond; top left panel only) as is Asn74 (ST8SiaIV numbering), the major site of autopolysialylation (square; only labeled in top left panel).
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Supplementary Figures 1–6 and Supplementary Table 1 (PDF 6047 kb)
Supplementary Data Set 1
LC-MS/MS analysis of glycosylated ST8SiaIII (PDF 4657 kb)
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Volkers, G., Worrall, L., Kwan, D. et al. Structure of human ST8SiaIII sialyltransferase provides insight into cell-surface polysialylation. Nat Struct Mol Biol 22, 627–635 (2015). https://doi.org/10.1038/nsmb.3060
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DOI: https://doi.org/10.1038/nsmb.3060
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