Kristallstruktur av dermatansulfat-epimeras 1 och utredning av dess interaktion med dermatan-sulfotransferas 1

Projekt: Övrigt



Proteoglycans (PGs) are integral components of the extracellular matrix and consist of a core protein with one or more covalently attached glycosaminoglycan (GAG) chains. A common GAG is chondroitin/dermatan sulfate (CS/DS) where the disaccharide repeating unit consists of a uronicacid, that is glucuronic acid (GlcA) or iduronic acid (IdoA), linked to an N-acetylated galactosamine (GalNAc). For IdoA-containing CS/DS chains, the first biosynthetic step after polymerization is epimerization of GlcA into IdoA. Our group has identified and cloned the two human CS/DS epimerases, dermatan sulfate epimerase 1 and -2 (DSE and DSEL). DSE is, by far, the most widely expressed of the two, and can be found throughout the body, except in serum. Subsequent sulfation by dermatan 4-O-sulfotransferase 1 (D4ST1), which transfers a sulfate to position four of GalNAc next to IdoA, is tightly coupled to epimerization.
We have shown that DSE yields only a few iduronic acid residues at a slow speed. However, co-incubation with D4ST1 increases the speed of epimerization five-fold. The enzymes have been cross-linked and larger complexes observed have been confirmed by mass spectrometry analysis to contain both DSE and D4ST1. Together, this suggests that DSE and D4ST1 interact during the formation of CS/DS. We hope that macromolecular crystallography experiments will yield information necessary to solve high-resolution structures of both enzymes, and for DSE together with its binding partner D4ST1. The information above can then be used to understand how the enzymes act during biosynthesis, as well as for rational design and chemical synthesis of sp
Gällande start-/slutdatum2018/05/082019/05/08


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