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Structure, substrate-recognition, and initiation of hyaluronan synthase

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Maloney, Finn P., Kuklewicz, Jeremi, Corey, Robin A., Bi, Yunchen, Ho, Ruoya, Mateusiak, Lukasz, Pardon, Els, Steyaert, Jan, Stansfeld, Phillip J. and Zimmer, Jochen (2022) Structure, substrate-recognition, and initiation of hyaluronan synthase. Nature, 604 . pp. 195-201. doi:10.1038/s41586-022-04534-2 ISSN 0028-0836.

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Official URL: https://doi.org/10.1038/s41586-022-04534-2

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Abstract

Hyaluronan is an acidic heteropolysaccharide comprising alternating N-acetylglucosamine and glucuronic acid sugars that is ubiquitously expressed in the vertebrate extracellular matrix1. The high-molecular-mass polymer modulates essential physiological processes in health and disease, including cell differentiation, tissue homeostasis and angiogenesis2. Hyaluronan is synthesized by a membrane-embedded processive glycosyltransferase, hyaluronan synthase (HAS), which catalyses the synthesis and membrane translocation of hyaluronan from uridine diphosphate-activated precursors3,4. Here we describe five cryo-electron microscopy structures of a viral HAS homologue at different states during substrate binding and initiation of polymer synthesis. Combined with biochemical analyses and molecular dynamics simulations, our data reveal how HAS selects its substrates, hydrolyses the first substrate to prime the synthesis reaction, opens a hyaluronan-conducting transmembrane channel, ensures alternating substrate polymerization and coordinates hyaluronan inside its transmembrane pore. Our research suggests a detailed model for the formation of an acidic extracellular heteropolysaccharide and provides insights into the biosynthesis of one of the most abundant and essential glycosaminoglycans in the human body.

Item Type: Journal Article
Subjects: Q Science > QD Chemistry
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Hyaluronic acid -- Synthesis, Hyaluronic acid -- Structure
Journal or Publication Title: Nature
Publisher: Nature Publishing
ISSN: 0028-0836
Official Date: 7 April 2022
Dates:
DateEvent
7 April 2022Published
30 March 2022Available
8 February 2022Accepted
Volume: 604
Page Range: pp. 195-201
DOI: 10.1038/s41586-022-04534-2
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Copyright Holders: The Author(s), under exclusive licence to Springer Nature Limited
Date of first compliant deposit: 8 February 2022
Date of first compliant Open Access: 30 September 2022
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
R21AI148853National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
R01GM101001National Institutes of Healthhttp://dx.doi.org/10.13039/100000002
208361/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
BB/P01948X/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/R002517/1 [BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/S003339/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
MR/S009213/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
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