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Search: WFRF:(Wilson Derek) > (2020-2024) > The structure of EX...

  • Wilson, L. F. L.University of Cambridge (author)

The structure of EXTL3 helps to explain the different roles of bi-domain exostosins in heparan sulfate synthesis

  • Article/chapterEnglish2022

Publisher, publication year, extent ...

  • 2022-06-08
  • Springer Science and Business Media LLC,2022

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:09ef3b08-9472-4af7-8fb3-a9a8b1413685
  • https://lup.lub.lu.se/record/09ef3b08-9472-4af7-8fb3-a9a8b1413685URI
  • https://doi.org/10.1038/s41467-022-31048-2DOI

Supplementary language notes

  • Language:English
  • Summary in:English &Swedish

Part of subdatabase

Classification

  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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.
  • 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Dendooven, T.University of Cambridge (author)
  • Hardwick, S. W.University of Cambridge (author)
  • Echevarría-Poza, A. (author)
  • Tryfona, T. (author)
  • Krogh, K. B. R. M.Novozymes A/S (author)
  • Chirgadze, D. Y. (author)
  • Luisi, B. F. (author)
  • Logan, Derek TLund University,Lunds universitet,Biokemi och Strukturbiologi,Centrum för Molekylär Proteinvetenskap,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Biochemistry and Structural Biology,Center for Molecular Protein Science,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH(Swepub:lu)mbfys-do (author)
  • Mani, KatrinLund University,Lunds universitet,Glykobiologigruppen,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Glycobiology,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments(Swepub:lu)medk-kma (author)
  • Dupree, P.University of Cambridge (author)
  • University of CambridgeNovozymes A/S (creator_code:org_t)

Related titles

  • In:Nature Communications: Springer Science and Business Media LLC13:33142041-1723

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