The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis
Published version
Peer-reviewed
Repository URI
Repository DOI
Type
Change log
Authors
Abstract
Abstract: 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 bi-domain 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 UDP-bound forms. We explain the ineffectiveness of EXTL3’s GT47 domain to transfer β-d-glucuronosyl 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.
Description
Funder: University of Cambridge; doi: https://doi.org/10.13039/501100000735
Funder: AstraZeneca; doi: https://doi.org/10.13039/100004325
Funder: RCUK | Biotechnology and Biological Sciences Research Council (BBSRC); doi: https://doi.org/10.13039/501100000268
Funder: RCUK | Engineering and Physical Sciences Research Council (EPSRC); doi: https://doi.org/10.13039/501100000266
Funder: OpenPlant, BB/L014130/1
Keywords
Journal Title
Conference Name
Journal ISSN
Volume Title
Publisher
Publisher DOI
Sponsorship
Vetenskapsrådet (Swedish Research Council) (2016-04855, 2014-03402)
Cancerfonden (Swedish Cancer Society) (21 1426 Pj 01 H)