Structural highlights
Disease
EXT1_HUMAN Chondrosarcoma;Multiple osteochondromas;Trichorhinophalangeal syndrome type 2. The disease is caused by variants affecting the gene represented in this entry. The gene represented in this entry is involved in disease pathogenesis. A chromosomal aberration resulting in the loss of functional copies of TRPS1 and EXT1 has been found in TRPS2 patients. The disease is caused by variants affecting the gene represented in this entry.
Function
EXT1_HUMAN Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413).[1] [2]
Publication Abstract from PubMed
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.
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, Coute Y, Bonnaffe D, Sadir R, Lortat-Jacob H, Wild R Nat Commun. 2022 Nov 19;13(1):7110. doi: 10.1038/s41467-022-34882-6. PMID:36402845[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Duncan G, McCormick C, Tufaro F. The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins. J Clin Invest. 2001 Aug;108(4):511-6. doi: 10.1172/JCI13737. PMID:11518722 doi:http://dx.doi.org/10.1172/JCI13737
- ↑ Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, Zimmermann P, David G. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012 Jun 3;14(7):677-85. doi: 10.1038/ncb2502. PMID:22660413 doi:http://dx.doi.org/10.1038/ncb2502
- ↑ Leisico F, Omeiri J, Le Narvor C, Beaudouin J, Hons M, Fenel D, Schoehn G, Coute Y, Bonnaffe D, Sadir R, Lortat-Jacob H, Wild R. Structure of the human heparan sulfate polymerase complex EXT1-EXT2. Nat Commun. 2022 Nov 19;13(1):7110. doi: 10.1038/s41467-022-34882-6. PMID:36402845 doi:http://dx.doi.org/10.1038/s41467-022-34882-6
