The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis
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Dupree, P., Wilson, l., Echevarria-poza, a., Dendooven, T., Hardwick, S., Tryfona, T., krogh, K., et al. (2022). The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis. Nature Communications https://doi.org/10.1038/s41467-022-31048-2
Heparan sulfate is a highly modified O-linked glycan that performs diverse physiological roles in animal tissues. Though quickly modified, it is initially synthesised as a polysaccharide of alternating β-D-glucuronosyl and N-acetyl-α-D-glucosaminyl residues by exostosins. These enzymes generally possess two glycosyltransferase domains (GT47 and GT64)—each thought to add one type of monosaccharide unit to the backbone. Although previous structures of murine exostosin-like 2 (EXTL2) provide insight into the GT64 domain, the rest of the bidomain architecture is yet to be characterised; hence, how the two domains co-operate is unknown. Here, we report the structure of human exostosin-like 3 (EXTL3) in apo and UDPbound forms. We explain the ineffectiveness of EXTL3’s GT47 domain to transfer β-Dglucuronosyl units, and we observe that, in general, the bi-domain architecture would preclude a processive mechanism of backbone extension. We therefore propose that heparan sulfate backbone polymerisation occurs by a simple dissociative mechanism.
This work was funded by grants from the University of Cambridge, BBSRC OpenPlant (BB/L014130/1, P.D.), the Swedish Research Council (2014-03402, K.M.; 2016-04855, D.T.L.), Cancerfonden (21 1426 Pj 01 H, K.M.), and the Wellcome Trust (200873/Z/16/Z, B.F.L.). L.F.L.W. was supported by the University of Cambridge. T.D. was supported by an AstraZeneca studentship.
Biotechnology and Biological Sciences Research Council (BB/L014130/1)
Wellcome Trust (200873/Z/16/Z)
External DOI: https://doi.org/10.1038/s41467-022-31048-2
This record's URL: https://www.repository.cam.ac.uk/handle/1810/338352
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/