Journal article
NMR Studies of Hexaacylated Endotoxin Bound to Wild-type and F126A Mutant MD-2 and MD-2.TLR4 Ectodomain Complexes
The Journal of biological chemistry, Vol.287(20), pp.16346-16355
05/11/2012
DOI: 10.1074/jbc.M112.343467
PMCID: PMC3351295
PMID: 22433852
Abstract
Host response to invasion by many Gram-negative bacteria depends upon activation of Toll-like receptor 4 (TLR4) by endotoxin presented as a monomer bound to myeloid differentiation factor 2 (MD-2). Metabolic labeling of hexaacylated endotoxin (LOS) from Neisseria meningitidis with [C-13]acetate allowed the use of NMR to examine structural properties of the fatty acyl chains of LOS present in TLR4-agonistic and -antagonistic binary and ternary complexes with, respectively, wild-type or mutant (F126A) MD-2 +/- TLR4 ectodomain. Chemical shift perturbation indicates that Phe(126) affects the environment and/or position of each of the bound fatty acyl chains both in the binary LOS.MD-2 complex and in the ternary LOS.MD-2.TLR4 ectodomain complex. In both wild-type and mutant LOS.MD-2 complexes, one of the six fatty acyl chains of LOS is more susceptible to paramagnetic attenuation, suggesting protrusion of that fatty acyl chain from the hydrophobic pocket of MD-2, independent of association with TLR4. These findings indicate that re-orientation of the aromatic side chain of Phe(126) is induced by binding of hexaacylated E, preceding interaction with TLR4. This re-arrangement of Phe(126) may act as a "hydrophobic switch," driving agonist-dependent contacts needed for TLR4 dimerization and activation.
Details
- Title: Subtitle
- NMR Studies of Hexaacylated Endotoxin Bound to Wild-type and F126A Mutant MD-2 and MD-2.TLR4 Ectodomain Complexes
- Creators
- Liping Yu - University of IowaRachel L. Phillips - University of IowaDeSheng Zhang - University of IowaAthmane Teghanemt - University of IowaJerrold P. Weiss - University of IowaTheresa L. Gioannini - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.287(20), pp.16346-16355
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- DOI
- 10.1074/jbc.M112.343467
- PMID
- 22433852
- PMCID
- PMC3351295
- eISSN
- 1083-351X
- Number of pages
- 10
- Grant note
- Dept. of Veterans' Affairs; US Department of Veterans Affairs R01AI059372 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) AI05732 / NIAID, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Language
- English
- Date published
- 05/11/2012
- Academic Unit
- Infectious Diseases; Biochemistry and Molecular Biology; Medicine Administration; Internal Medicine
- Record Identifier
- 9984627300302771
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