Heparan sulfates are long and highly complex polysaccharide chains found on the cell surface and in the extra cellular matrix. They play a key role in many biological process including cell development, signaling and immune responses but also in pathogenic infections like with SARS-CoV-2. A central step in the biosynthesis of heparan sulfate is the generation of the long glycan backbone, consisting of N-acetylglucosmanine and glucuronic acid units. Two enzymes, EXT1 and EXT2, haven been previously shown to carry out heparan sulfate chain elongation, the molecular mechanism, however, remained unknown.
The SAGAG group, in collaboration with researchers from the Université Paris-Saclay, the IBS, EMBL and BioSanté in Grenoble, provide in their manuscript a detailed functional and structural analysis of the EXT1 and EXT2 enzymes. A cryo-electron microscopy structure reveals that the two enzymes form a tightly packed hetero-dimeric enzyme complex and in vitro and in cellulo functional assays were used to dissect the catalytic activities of the four glycosyltransferase domains. Surprisingly, these catalytic sites are facing away of each other, suggesting that chain polymerization is a non-processive process. The obtained insights provide a rational for mutations observed in patients suffering from hereditary multiple exostoses and might guide the future development of drugs to regulate heparan sulfate biosynthesis in order to treat cancer and viral infections.
Structure of the human heparan sulfate polymerase complex EXT1-EXT2. Leisico F, Omeiri J, Le Narvor C, Beaudouin J, Hons M, Fenel D, Schoehn G, Couté Y, Bonnaffé D, Sadir R, Lortat-Jacob H, Wild R. Nature Communications (2022) ; 13(1):7110
Contact : Rebekka Wild (IBS/Structure and Activity of Glycosaminoglycans Group)