University of Oulu

Emil Tykesson, Antti Hassinen, Katarzyna Zielinska, Martin A. Thelin, Giacomo Frati, Ulf Ellervik, Gunilla Westergren-Thorsson, Anders Malmström, Sakari Kellokumpu, Marco Maccarana, Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks, Journal of Biological Chemistry, Volume 293, Issue 35, 2018, Pages 13725-13735, ISSN 0021-9258,

Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks

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Author: Tykesson, Emil1; Hassinen, Antti2,3; Zielinska, Katarzyna1;
Organizations: 1Department of Experimental Medical Science, Lund University, SE-221 00, Lund, Sweden
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90570 Oulu, Finland
3Institute for Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland
4Department of Chemistry, Lund University, SE-221 00, Lund, Sweden
Format: article
Version: published version
Access: open
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Language: English
Published: American Society for Biochemistry and Molecular Biology, 2018
Publish Date: 2021-06-30


During the biosynthesis of chondroitin/dermatan sulfate (CS/DS), a variable fraction of glucuronic acid is converted to iduronic acid through the activities of two epimerases, dermatan sulfate epimerases 1 (DS-epi1) and 2 (DS-epi2). Previous in vitro studies indicated that without association with other enzymes, DS-epi1 activity produces structures that have only a few adjacent iduronic acid units. In vivo, concomitant with epimerization, dermatan 4-O-sulfotransferase 1 (D4ST1) sulfates the GalNAc adjacent to iduronic acid. This sulfation facilitates DS-epi1 activity and enables the formation of long blocks of sulfated iduronic acid–containing domains, which can be major components of CS/DS. In this report, we used recombinant enzymes to confirm the concerted action of DS-epi1 and D4ST1. Confocal microscopy revealed that these two enzymes colocalize to the Golgi, and FRET experiments indicated that they physically interact. Furthermore, FRET, immunoprecipitation, and cross-linking experiments also revealed that DS-epi1, DS-epi2, and D4ST1 form homomers and are all part of a hetero-oligomeric complex where D4ST1 directly interacts with DS-epi1, but not with DS-epi2. The cooperation of DS-epi1 with D4ST1 may therefore explain the processive mode of the formation of iduronic acid blocks. In conclusion, the iduronic acid–forming enzymes operate in complexes, similar to other enzymes active in glycosaminoglycan biosynthesis. This knowledge shed light on regulatory mechanisms controlling the biosynthesis of the structurally diverse CS/DS molecule.

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Series: Journal of biological chemistry
ISSN: 0021-9258
ISSN-E: 1083-351X
ISSN-L: 0021-9258
Volume: 293
Issue: 35
Pages: 13725 - 13735
DOI: 10.1074/jbc.RA118.003875
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
Copyright information: © 2018 Tykesson et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an open access article under the CC BY license.