化学
透明质酸合成酶
生物化学
基质(水族馆)
跨膜蛋白
糖基转移酶
细胞外
生物物理学
膜
生物合成
糖胺聚糖
细胞外基质
酶
细胞生物学
生物
受体
生态学
作者
Finn P. Maloney,Jeremi Kuklewicz,Robin A. Corey,Yunchen Bi,Ruoya Ho,Łukasz Mateusiak,Els Pardon,Jan Steyaert,Phillip J. Stansfeld,Jochen Zimmer
出处
期刊:Nature
[Springer Nature]
日期:2022-03-30
卷期号:604 (7904): 195-201
被引量:70
标识
DOI:10.1038/s41586-022-04534-2
摘要
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. A cryo-electron microscopy analysis reveals 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.
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