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Structural highlights

Disease

EXT1_HUMAN Trichorhinophalangeal syndrome type 2;Chondrosarcoma;Multiple osteochondromas. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

EXT1_HUMAN Glycosyltransferase forming with EXT2 the heterodimeric heparan sulfate polymerase which catalyzes the elongation of the heparan sulfate glycan backbone (PubMed:10639137, PubMed:22660413, PubMed:36402845, PubMed:36593275, PubMed:9620772). Glycan backbone extension consists in the alternating transfer of (1->4)-beta-D-GlcA and (1->4)-alpha-D-GlcNAc residues from their respective UDP-sugar donors. Both EXT1 and EXT2 are required for the full activity of the polymerase since EXT1 bears the N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity within the complex while EXT2 carries the glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity (PubMed:36402845, PubMed:36593275). Heparan sulfate proteoglycans are ubiquitous components of the extracellular matrix and play an important role in tissue homeostasis and signaling (PubMed:10639137, PubMed:11391482, PubMed:22660413, PubMed:9620772).^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ McCormick C, Duncan G, Goutsos KT, Tufaro F. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate. Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):668-73. PMID:10639137 doi:10.1073/pnas.97.2.668
2. ↑ Cheung PK, McCormick C, Crawford BE, Esko JD, Tufaro F, Duncan G. Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Am J Hum Genet. 2001 Jul;69(1):55-66. PMID:11391482 doi:10.1086/321278
3. ↑ 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
4. ↑ 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
5. ↑ Li H, Chapla D, Amos RA, Ramiah A, Moremen KW, Li H. Structural basis for heparan sulfate co-polymerase action by the EXT1-2 complex. Nat Chem Biol. 2023 May;19(5):565-574. PMID:36593275 doi:10.1038/s41589-022-01220-2
6. ↑ McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 1998 Jun;19(2):158-61. PMID:9620772 doi:10.1038/514
7. ↑ 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