Structure of the human heparan sulfate polymerase complex EXT1-EXT2

Francisco Leisico, Juneina Omeiri, Christine Narvor, Joël Beaudouin, Michael Hons, Daphna Fenel, Guy Schoehn, Yohann Couté, David Bonnaffé, Rabia Sadir, Hugues Lortat-Jacob () and Rebekka Wild ()
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Francisco Leisico: University Grenoble Alpes, CNRS, CEA
Juneina Omeiri: University Grenoble Alpes, CNRS, CEA
Christine Narvor: Université Paris-Saclay, CNRS, Institut de chimie moléculaire et des matériaux d’Orsay
Joël Beaudouin: University Grenoble Alpes, CNRS, CEA
Michael Hons: Grenoble Outstation
Daphna Fenel: University Grenoble Alpes, CNRS, CEA
Guy Schoehn: University Grenoble Alpes, CNRS, CEA
Yohann Couté: University Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, FR2048
David Bonnaffé: Université Paris-Saclay, CNRS, Institut de chimie moléculaire et des matériaux d’Orsay
Rabia Sadir: University Grenoble Alpes, CNRS, CEA
Hugues Lortat-Jacob: University Grenoble Alpes, CNRS, CEA
Rebekka Wild: University Grenoble Alpes, CNRS, CEA

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Heparan sulfates are complex polysaccharides that mediate the interaction with a broad range of protein ligands at the cell surface. A key step in heparan sulfate biosynthesis is catalyzed by the bi-functional glycosyltransferases EXT1 and EXT2, which generate the glycan backbone consisting of repeating N-acetylglucosamine and glucuronic acid units. The molecular mechanism of heparan sulfate chain polymerization remains, however, unknown. Here, we present the cryo-electron microscopy structure of human EXT1-EXT2, which reveals the formation of a tightly packed hetero-dimeric complex harboring four glycosyltransferase domains. A combination of in vitro and in cellulo mutational studies is used to dissect the functional role of the four catalytic sites. While EXT1 can catalyze both glycosyltransferase reactions, our results indicate that EXT2 might only have N-acetylglucosamine transferase activity. Our findings provide mechanistic insight into heparan sulfate chain elongation as a nonprocessive process and lay the foundation for future studies on EXT1-EXT2 function in health and disease.

Date: 2022
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DOI: 10.1038/s41467-022-34882-6

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