7uqx

From Proteopedia

Jump to: navigation, search

Cryo-EM structure of the human Exostosin-1 and Exostosin-2 heterodimer in complex with UDP-GlcNAc

Structural highlights

7uqx is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.3Å
Ligands:BMA, MN, NAG, UDP
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Heparan 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.

Loading citation details..
Citations
3 reviews cite this structure
Global impact of proteoglycan science on human diseases.
Xie et al. (2023)
2 more
6 other articles
No citations found

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. ↑ 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

Contents


PDB ID 7uqx

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://proteopedia.org/wiki/index.php/7uqx"
Personal tools