The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms
(2021) In Chemical Science 12(5). p.1869-1885- Abstract
Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture,... (More)
Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.
(Less)
- author
- organization
-
- Biochemistry and Structural Biology
- BioMS (research group)
- Molecular Pathogenesis (research group)
- LUBIN Lab- Lund Brain Injury laboratory for Neurosurgical research (research group)
- Centre for Analysis and Synthesis
- Biotechnology
- epIgG (research group)
- SEBRA Sepsis and Bacterial Resistance Alliance (research group)
- Infection Medicine Proteomics (research group)
- WCMM-Wallenberg Centre for Molecular Medicine
- Lund University Bioimaging Center
- Lung Biology (research group)
- Matrix Biology (research group)
- publishing date
- 2021-02-07
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Chemical Science
- volume
- 12
- issue
- 5
- pages
- 17 pages
- publisher
- Royal Society of Chemistry
- external identifiers
-
- pmid:33815739
- scopus:85101166678
- ISSN
- 2041-6520
- DOI
- 10.1039/d0sc05971d
- project
- Small molecules that interfere with the biosynthesis of dermatan sulfate for exploration of cell surface carbohydrates and use as cancer therapy
- language
- English
- LU publication?
- yes
- id
- 7f5e95b2-2227-428e-9353-e25b4e07f4f0
- date added to LUP
- 2021-03-10 17:07:54
- date last changed
- 2024-09-05 16:45:54
@article{7f5e95b2-2227-428e-9353-e25b4e07f4f0, abstract = {{<p>Dermatan sulfate epimerase 1 (DS-epi1, EC 5.1.3.19) catalyzes the conversion of d-glucuronic acid to l-iduronic acid on the polymer level, a key step in the biosynthesis of the glycosaminoglycan dermatan sulfate. Here, we present the first crystal structure of the catalytic domains of DS-epi1, solved at 2.4 Å resolution, as well as a model of the full-length luminal protein obtained by a combination of macromolecular crystallography and targeted cross-linking mass spectrometry. Based on docking studies and molecular dynamics simulations of the protein structure and a chondroitin substrate, we suggest a novel mechanism of DS-epi1, involving a His/double-Tyr motif. Our work uncovers detailed information about the domain architecture, active site, metal-coordinating center and pattern of N-glycosylation of the protein. Additionally, the structure of DS-epi1 reveals a high structural similarity to proteins from several families of bacterial polysaccharide lyases. DS-epi1 is of great importance in a range of diseases, and the structure provides a necessary starting point for design of active site inhibitors.</p>}}, author = {{Hasan, Mahmudul and Khakzad, Hamed and Happonen, Lotta and Sundin, Anders and Unge, Johan and Mueller, Uwe and Malmström, Johan and Westergren-Thorsson, Gunilla and Malmström, Lars and Ellervik, Ulf and Malmström, Anders and Tykesson, Emil}}, issn = {{2041-6520}}, language = {{eng}}, month = {{02}}, number = {{5}}, pages = {{1869--1885}}, publisher = {{Royal Society of Chemistry}}, series = {{Chemical Science}}, title = {{The structure of human dermatan sulfate epimerase 1 emphasizes the importance of C5-epimerization of glucuronic acid in higher organisms}}, url = {{http://dx.doi.org/10.1039/d0sc05971d}}, doi = {{10.1039/d0sc05971d}}, volume = {{12}}, year = {{2021}}, }