7scj
From Proteopedia
Cryo-EM structure of the human Exostosin-1 and Exostosin-2 heterodimer in complex with a 4-sugar oligosaccharide acceptor analog
Structural highlights
DiseaseEXT1_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. FunctionEXT1_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] Publication Abstract from PubMedHeparan sulfate (HS) proteoglycans are extended (-GlcAbeta1,4GlcNAcalpha1,4-)(n) co-polymers containing decorations of sulfation and epimerization that are linked to cell surface and extracellular matrix proteins. In mammals, HS repeat units are extended by an obligate heterocomplex of two exostosin family members, EXT1 and EXT2, where each protein monomer contains distinct GT47 (GT-B fold) and GT64 (GT-A fold) glycosyltransferase domains. In this study, we generated human EXT1-EXT2 (EXT1-2) as a functional heterocomplex and determined its structure in the presence of bound donor and acceptor substrates. Structural data and enzyme activity of catalytic site mutants demonstrate that only two of the four glycosyltransferase domains are major contributors to co-polymer syntheses: the EXT1 GT-B fold beta1,4GlcA transferase domain and the EXT2 GT-A fold alpha1,4GlcNAc transferase domain. The two catalytic sites are over 90 A apart, indicating that HS is synthesized by a dissociative process that involves a single catalytic site on each monomer. Structural basis for heparan sulfate co-polymerase action by the EXT1-2 complex.,Li H, Chapla D, Amos RA, Ramiah A, Moremen KW, Li H Nat Chem Biol. 2023 May;19(5):565-574. doi: 10.1038/s41589-022-01220-2. Epub 2023 , Jan 2. PMID:36593275[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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