Structure, substrate recognition and initiation of hyaluronan synthase

Finn P. Maloney, Jeremi Kuklewicz, Robin A. Corey, Yunchen Bi, Ruoya Ho, Lukasz Mateusiak, Els Pardon, Jan Steyaert, Phillip J. Stansfeld and Jochen Zimmer ()
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Finn P. Maloney: University of Virginia School of Medicine
Jeremi Kuklewicz: University of Virginia School of Medicine
Robin A. Corey: University of Oxford
Yunchen Bi: Pilot National Laboratory for Marine Science and Technology (Qingdao)
Ruoya Ho: University of Virginia School of Medicine
Lukasz Mateusiak: ICMI-BEFY, Vrije Universiteit Brussel
Els Pardon: VIB
Jan Steyaert: VIB
Phillip J. Stansfeld: University of Warwick
Jochen Zimmer: University of Virginia School of Medicine

Nature, 2022, vol. 604, issue 7904, 195-201

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-04534-2

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