University of Oulu

Deborah Harrus, Anne Harduin-Lepers, Tuomo Glumoff, Unliganded and CMP-Neu5Ac bound structures of human α-2,6-sialyltransferase ST6Gal I at high resolution, Journal of Structural Biology, Volume 212, Issue 2, 2020, 107628, ISSN 1047-8477, https://doi.org/10.1016/j.jsb.2020.107628

Unliganded and CMP-Neu5Ac bound structures of human α-2,6-sialyltransferase ST6Gal I at high resolution

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Author: Harrus, Deborah1,2; Harduin-Lepers, Anne3; Glumoff, Tuomo1
Organizations: 1Faculty of Biochemistry and Molecular Medicine, University of Oulu, Aapistie 7A, FI-90220 Oulu, Finland
2Current address: Protein Data Bank in Europe, European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge CB10 1SD, UK
3Université de Lille, CNRS, UMR 8576-UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, F-59000 Lille, France
Format: article
Version: accepted version
Access: embargoed
Persistent link: http://urn.fi/urn:nbn:fi-fe2020100277771
Language: English
Published: Elsevier, 2020
Publish Date: 2021-09-21
Description:

Abstract

Sialic acid residues found as terminal monosaccharides in various types of glycan chains in cell surface glycoproteins and glycolipids have been identified as important contributors of cell-cell interactions in normal vs. abnormal cellular behavior and are pivotal in diseases such as cancers. In vertebrates, sialic acids are attached to glycan chains by a conserved subset of sialyltransferases with different enzymatic and substrate specificities. ST6Gal I is a sialyltransferase using activated CMP-sialic acids as donor substrates to catalyze the formation of a α2,6-glycosidic bond between the sialic acid residue and the acceptor disaccharide LacNAc. Understanding sialyltransferases at the molecular and structural level shed light into their function. We present here two human ST6Gal I structures, which show for the first time the enzyme in the unliganded state and with the full donor substrate CMP-Neu5Ac bound. Comparison of these structures reveal flexibility of the catalytic loop, since in the unliganded structure Tyr354 adopts a conformation seen also as an alternate conformation in the substrate bound structure. CMP-Neu5Ac is bound with the side chain at C5 of the sugar residue directed outwards at the surface of the protein. Furthermore, the exact binding mode of the sialic acid moiety of the substrate directly involves sialylmotifs L, S and III and positions the sialylmotif VS in the immediate vicinity. We also present a model for the ternary complex of ST6Gal I with both the donor and the acceptor substrates.

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Series: Journal of structural biology
ISSN: 1047-8477
ISSN-E: 1095-8657
ISSN-L: 1047-8477
Volume: 212
Issue: 2
Article number: 107628
DOI: 10.1016/j.jsb.2020.107628
OADOI: https://oadoi.org/10.1016/j.jsb.2020.107628
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Subjects:
Funding: We acknowledge the European Synchrotron Radiation Facility for provision of synchrotron radiation facilities, and we would like to thank the local contacts for providing assistance in using the beamlines ID30A-3 and ID23-1 (proposals MX1850 and MX1933). This work was carried out with the support of Biocenter Oulu, Structural Biology Core Facility, University of Oulu, Finland. We thank Rik Wierenga for fruitful discussions and critical reading of the manuscript. This work has been funded by the Academy of Finland (no. 285232) and University of Oulu, and also facilitated by University of Oulu short-term international research visits fund and the support provided jointly by the Institut Français de Finlande, the Embassy of France in Finland, the French Ministry of Education, Higher Education and Research, and the Finnish Society of Science and Letters.
Academy of Finland Grant Number: 285232
Detailed Information: 285232 (Academy of Finland Funding decision)
Copyright information: © 2020 Elsevier B.V. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
  https://creativecommons.org/licenses/by-nc-nd/4.0/