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

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Tykesson , E , Hassinen , A , Zielinska , K , Thelin , M A , Frati , G , Ellervik , U , Westergren-Thorsson , G , Malmström , A , Kellokumpu , S & Maccarana , M 2018 , ' Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks ' , Journal of Biological Chemistry , vol. 293 , no. 35 , pp. 13725-13735 . https://doi.org/10.1074/jbc.RA118.003875

Title: Dermatan sulfate epimerase 1 and dermatan 4-O-sulfotransferase 1 form complexes that generate long epimerized 4-O-sulfated blocks
Author: Tykesson, Emil; Hassinen, Antti; Zielinska, Katarzyna; Thelin, Martin A.; Frati, Giacomo; Ellervik, Ulf; Westergren-Thorsson, Gunilla; Malmström, Anders; Kellokumpu, Sakari; Maccarana, Marco
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
Date: 2018-08-31
Language: eng
Number of pages: 11
Belongs to series: Journal of Biological Chemistry
ISSN: 0021-9258
URI: http://hdl.handle.net/10138/246612
Abstract: 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.
Subject: chondroitin sulfate
dermatan sulfate
Golgi
glycosaminoglycan
glycobiology
D4ST1
DS-epi1
DS-epi2
epimerization
epimerase
EHLERS-DANLOS-SYNDROME
GROWTH FACTOR/SCATTER FACTOR
HEPARIN-COFACTOR-II
CHONDROITIN SULFATE
IDURONIC ACID
CANCER-CELLS
BIOSYNTHESIS
SUBSTRATE
N-ACETYLGALACTOSAMINYLTRANSFERASE-1
POLYMERIZATION
3111 Biomedicine
1182 Biochemistry, cell and molecular biology
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