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Structure of the human heparan sulfate polymerase complex EXT1-EXT2.
Leisico, Francisco; Omeiri, Juneina; Le Narvor, Christine; Beaudouin, Joël; Hons, Michael; Fenel, Daphna; Schoehn, Guy; Couté, Yohann; Bonnaffé, David; Sadir, Rabia; Lortat-Jacob, Hugues; Wild, Rebekka.
Afiliación
  • Leisico F; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Omeiri J; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Le Narvor C; Université Paris-Saclay, CNRS, Institut de chimie moléculaire et des matériaux d'Orsay, 91405, Orsay, France.
  • Beaudouin J; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Hons M; European Molecular Biology Laboratory (EMBL), Grenoble Outstation, 71 avenue des Martyrs, 38042, Grenoble, France.
  • Fenel D; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Schoehn G; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Couté Y; University Grenoble Alpes, INSERM, CEA, UMR BioSanté U1292, CNRS, CEA, FR2048, 38000, Grenoble, France.
  • Bonnaffé D; Université Paris-Saclay, CNRS, Institut de chimie moléculaire et des matériaux d'Orsay, 91405, Orsay, France.
  • Sadir R; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France.
  • Lortat-Jacob H; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France. Hugues.Lortat-Jacob@ibs.fr.
  • Wild R; Institut de Biologie Structurale, UMR 5075, University Grenoble Alpes, CNRS, CEA, 38000, Grenoble, France. Rebekka.Wild@ibs.fr.
Nat Commun ; 13(1): 7110, 2022 11 19.
Article en En | MEDLINE | ID: mdl-36402845
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: N-Acetilglucosaminiltransferasas / Heparitina Sulfato Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: N-Acetilglucosaminiltransferasas / Heparitina Sulfato Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2022 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Reino Unido