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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
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Official URL: https://doi.org/10.1038/s41586-022-04534-2
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 | ||||||||||||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QP Physiology |
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| 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 | ||||||||||||||||||||||||
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| 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 | ||||||||||||||||||||||||
| RIOXX Funder/Project Grant: |
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