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Shah NR, Albitar-Nehme S, Kim E, Marr N, Novikov A, Caroff M, Fernandez RC
Minor modifications to the phosphate groups and the C3' acyl chain length of lipid A in two Bordetella pertussis strains, BP338 and 18-323, independently affect Toll-like receptor 4 protein activation
Journal of Biological Chemistry 288(17) (2013)
11751-11760
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3HODco-(1-3)-+
|
?%a-D-GlcpN-(1--P--1)--+ |
| |
?%a-D-GlcpN-(1--P--4)--+ | |
| | |
Myr-(1-3)-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN
| |
3HOMyr-(1-3)-+ 3HOMyr-(1-2)-+ |
Show graphically |
Bordetella pertussis BP338
(Ancestor NCBI TaxID 520,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: infection due to Bordetella pertussis [ICD11:
XN23B 
]
The structure was elucidated in this paperNCBI PubMed ID: 23467413Publication DOI: 10.1074/jbc.M112.434365Journal NLM ID: 2985121RPublisher: Baltimore, MD: American Society for Biochemistry and Molecular Biology
Correspondence: rachelf
mail.ubc.ca
Institutions: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, Equipe Structure et Activités des Endotoxines, UMR 8621 du Centre National de la Recherche Scientifique, Institut de Génétique et Microbiologie (IGM), Université de Paris-Sud, 91405 Orsay cedex, France
Lipopolysaccharides (LPS) of Bordetella pertussis are important modulators of the immune system. Interaction of the lipid A region of LPS with the Toll-like receptor 4 (TLR4) complex causes dimerization of TLR4 and activation of downstream nuclear factor kappaB (NFkappaB), which can lead to inflammation. We have previously shown that two strains of B. pertussis, BP338 (a Tohama I-derivative) and 18-323, display two differences in lipid A structure. 1) BP338 can modify the 1- and 4'-phosphates by the addition of glucosamine (GlcN), whereas 18-323 cannot, and 2) the C3' acyl chain in BP338 is 14 carbons long, but only 10 or 12 carbons long in 18-323. In addition, BP338 lipid A can activate TLR4 to a greater extent than 18-323 lipid A. Here we set out to determine the genetic reasons for the differences in these lipid A structures and the contribution of each structural difference to the ability of lipid A to activate TLR4. We show that three genes of the lipid A GlcN modification (Lgm) locus, lgmA, lgmB, and lgmC (previously locus tags BP0399-BP0397), are required for GlcN modification and a single amino acid difference in LpxA is responsible for the difference in C3' acyl chain length. Furthermore, by introducing lipid A-modifying genes into 18-323 to generate isogenic strains with varying penta-acyl lipid A structures, we determined that both modifications increase TLR4 activation, although the GlcN modification plays a dominant role. These results shed light on how TLR4 may interact with penta-acyl lipid A species.
Lipopolysaccharide, structure, genetics, lipid A, Bordetella pertussis, lpxA, Toll-like receptor 4
Structure type: oligomer ; 1881 [M-H]-
Location inside paper: p.11755, fig.1C
Compound class: lipid A
Contained glycoepitopes: IEDB_137340,IEDB_141807,IEDB_151531,IEDB_176772
Methods: PCR, DNA techniques, MALDI-MS, genetic methods, statistical analysis, bioinformatic analysis, SDS-Tricine-PAGE, HEK-blue TLR4 activation assay
Biological activity: interaction lipid A structures with the TLR4-MD2 complex
Biosynthesis and genetic data: genetic data
Related record ID(s): 32044
NCBI Taxonomy refs (TaxIDs): 520
Show glycosyltransferases
There is only one chemically distinct structure:
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Shah NR, Albitar-Nehme S, Kim E, Marr N, Novikov A, Caroff M, Fernandez RC
Minor modifications to the phosphate groups and the C3' acyl chain length of lipid A in two Bordetella pertussis strains, BP338 and 18-323, independently affect Toll-like receptor 4 protein activation
Journal of Biological Chemistry 288(17) (2013)
11751-11760
|
3HOMyr-(1-3)-+ 3HOMyr-(1-2)-+
| |
Myr-(1-3)-3HOMyr-(1-2)-b-D-GlcpN-(1-6)-a-D-GlcpN-(1-P
| |
P-4)-+ 3HODco-(1-3)-+ |
Show graphically |
Bordetella pertussis BP338LgmABCDKO
(Ancestor NCBI TaxID 520,
species name lookup)
Taxonomic group: bacteria / Proteobacteria
(Phylum: Proteobacteria)
Associated disease: infection due to Bordetella pertussis [ICD11:
XN23B ]
The structure was elucidated in this paperNCBI PubMed ID: 23467413Publication DOI: 10.1074/jbc.M112.434365Journal NLM ID: 2985121RPublisher: Baltimore, MD: American Society for Biochemistry and Molecular Biology
Correspondence: rachelf
mail.ubc.ca
Institutions: Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada, Equipe Structure et Activités des Endotoxines, UMR 8621 du Centre National de la Recherche Scientifique, Institut de Génétique et Microbiologie (IGM), Université de Paris-Sud, 91405 Orsay cedex, France
Lipopolysaccharides (LPS) of Bordetella pertussis are important modulators of the immune system. Interaction of the lipid A region of LPS with the Toll-like receptor 4 (TLR4) complex causes dimerization of TLR4 and activation of downstream nuclear factor kappaB (NFkappaB), which can lead to inflammation. We have previously shown that two strains of B. pertussis, BP338 (a Tohama I-derivative) and 18-323, display two differences in lipid A structure. 1) BP338 can modify the 1- and 4'-phosphates by the addition of glucosamine (GlcN), whereas 18-323 cannot, and 2) the C3' acyl chain in BP338 is 14 carbons long, but only 10 or 12 carbons long in 18-323. In addition, BP338 lipid A can activate TLR4 to a greater extent than 18-323 lipid A. Here we set out to determine the genetic reasons for the differences in these lipid A structures and the contribution of each structural difference to the ability of lipid A to activate TLR4. We show that three genes of the lipid A GlcN modification (Lgm) locus, lgmA, lgmB, and lgmC (previously locus tags BP0399-BP0397), are required for GlcN modification and a single amino acid difference in LpxA is responsible for the difference in C3' acyl chain length. Furthermore, by introducing lipid A-modifying genes into 18-323 to generate isogenic strains with varying penta-acyl lipid A structures, we determined that both modifications increase TLR4 activation, although the GlcN modification plays a dominant role. These results shed light on how TLR4 may interact with penta-acyl lipid A species.
Lipopolysaccharide, structure, genetics, lipid A, Bordetella pertussis, lpxA, Toll-like receptor 4
Structure type: oligomer ; 1559 [M-H]-
Location inside paper: p.11755, fig.1D
Compound class: lipid A
Contained glycoepitopes: IEDB_135394,IEDB_137340,IEDB_141807,IEDB_151531,IEDB_176772
Methods: PCR, DNA techniques, MALDI-MS, genetic methods, statistical analysis, bioinformatic analysis, SDS-Tricine-PAGE, HEK-blue TLR4 activation assay
Biological activity: interaction lipid A structures with the TLR4-MD2 complex
Biosynthesis and genetic data: genetic data
Comments, role: mutant strain
Related record ID(s): 29342
NCBI Taxonomy refs (TaxIDs): 520
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There is only one chemically distinct structure:
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