FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / J Immunol / Elucidation of the MD-2/TLR4 interface required for signalin...
Journal of immunology (Baltimore, Md. : 1950)2008; 181(2); 1245-1254; doi: 10.4049/jimmunol.181.2.1245

Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa.

Abstract: LPS signals through a membrane bound-complex of the lipid binding protein MD-2 and the receptor TLR4. In this study we identify discrete regions in both MD-2 and TLR4 that are required for signaling by lipid IVa, an LPS derivative that is an agonist in horse but an antagonist in humans. We show that changes in the electrostatic surface potential of both MD-2 and TLR4 are required in order that lipid IVa can induce signaling. In MD-2, replacing horse residues 57-66 and 82-89 with the equivalent human residues confers a level of constitutive activity on horse MD-2, suggesting that conformational switching in this protein is likely to be important in ligand-induced activation of MD-2/TLR4. We identify leucine-rich repeat 14 in the C terminus of TLR4 as essential for lipid IVa activation of MD-2/TLR4. Remarkably, we identify a single residue in the glycan-free flank of the horse TLR4 solenoid that confers the ability to signal in response to lipid IVa. These results suggest a mechanism of signaling that involves crosslinking mediated by both MD-2-receptor and receptor-receptor contacts in a model that shows striking similarities to the recently published structure (Cell 130: 1071-1082) of the ligand-bound TLR1/2 ectodomain heterodimer.
Get Full Text
Publication Date: 2008-07-09 PubMed ID: 18606678DOI: 10.4049/jimmunol.181.2.1245Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article
  • Research Support
  • Non-U.S. Gov't

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research investigates how the signaling mechanism between MD-2, a lipid-binding protein, and TLR4, a receptor in the immune system, is affected by lipid IVa, a derivative of LPS (a compound found in bacterial cell walls). It pinpoints specific areas in MD-2 and TLR4 necessary for signaling, and suggests a signaling model involving contact between multiple receptors.

Understanding MD-2/TLR4 and Lipid IVa

  • The research focuses on the interaction between two proteins, MD-2 and TLR4. These proteins function together on the cell surface and play a crucial role in the body’s immune response.
  • Lipid IVa, a derivative of LPS (lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria), plays a dual role in this domain. It acts as an agonist (activator) in horses but as an antagonist (blocker) in humans.

Key Findings with MD-2 and TLR4

  • The research identifies specific regions in both MD-2 and TLR4 that are necessary for signaling by lipid IVa. Certain changes in the electrostatic surface potential of both MD-2 and TLR4 are required for lipid IVa to induce signaling.
  • In MD-2, replacing certain horse residue sequences with the equivalent human residue sequences confers a level of self-activity, suggesting significant conformational switching in MD-2 is likely involved in activation of the MD-2/TLR4 complex by ligands (molecules that bind to another molecule).

Significance in TLR4 and Signaling Mechanism

  • The leucine-rich repeat 14 in the C terminus (the end part) of TLR4 is found essential for lipid IVa activation of the MD-2/TLR4 complex. A single residue in the glycan-free flank of the horse TLR4 solenoid was found to confer the ability to signal in response to lipid IVa.
  • These results suggest a mechanism of signaling that involves the crosslinking mediated by contacts between both MD-2 and its receptor, as well as between multiple receptors.
  • In terms of broader biological functions, this signaling model shows remarkable similarities to the structure of the ligand-bound TLR1/2 ectodomain heterodimer, another protein complex crucial in cellular communication.

Cite This Article

APA
Walsh C, Gangloff M, Monie T, Smyth T, Wei B, McKinley TJ, Maskell D, Gay N, Bryant C. (2008). Elucidation of the MD-2/TLR4 interface required for signaling by lipid IVa. J Immunol, 181(2), 1245-1254. https://doi.org/10.4049/jimmunol.181.2.1245

Publication

Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
NlmUniqueID: 2985117R
Country: United States
Language: English
Volume: 181
Issue: 2
Pages: 1245-1254

Researcher Affiliations

Walsh, Catherine
  • Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Gangloff, Monique
    Monie, Tom
      Smyth, Tomoko
        Wei, Bin
          McKinley, Trevelyan J
            Maskell, Duncan
              Gay, Nicholas
                Bryant, Clare

                  MeSH Terms

                  • Amino Acid Sequence
                  • Animals
                  • Cats
                  • Cell Line
                  • Glycolipids / immunology
                  • Glycolipids / metabolism
                  • Horses
                  • Humans
                  • Ligands
                  • Lipid A / analogs & derivatives
                  • Lipid A / immunology
                  • Lipid A / metabolism
                  • Lipopolysaccharide Receptors / immunology
                  • Lipopolysaccharide Receptors / metabolism
                  • Lymphocyte Antigen 96 / chemistry
                  • Lymphocyte Antigen 96 / genetics
                  • Lymphocyte Antigen 96 / immunology
                  • Lymphocyte Antigen 96 / metabolism
                  • Mice
                  • Molecular Sequence Data
                  • Point Mutation
                  • Protein Conformation
                  • Recombinant Fusion Proteins / immunology
                  • Recombinant Fusion Proteins / metabolism
                  • Sequence Alignment
                  • Signal Transduction
                  • Species Specificity
                  • Surface Properties
                  • Toll-Like Receptor 4 / chemistry
                  • Toll-Like Receptor 4 / genetics
                  • Toll-Like Receptor 4 / immunology
                  • Toll-Like Receptor 4 / metabolism

                  Grant Funding

                  • G0400007 / Medical Research Council
                  • G1000133 / Medical Research Council

                  Citations

                  This article has been cited 67 times.
                  1. Vinkler M, Fiddaman SR, Těšický M, O'Connor EA, Savage AE, Lenz TL, Smith AL, Kaufman J, Bolnick DI, Davies CS, Dedić N, Flies AS, Samblás MMG, Henschen AE, Novák K, Palomar G, Raven N, Samaké K, Slade J, Veetil NK, Voukali E, Höglund J, Richardson DS, Westerdahl H. Understanding the evolution of immune genes in jawed vertebrates.. J Evol Biol 2023 Jun;36(6):847-873.
                    doi: 10.1111/jeb.14181pubmed: 37255207google scholar: lookup
                  2. Mukhopadhyay A, Cook SR, SanMiguel P, Ekenstedt KJ, Taylor SD. TLR4 and MD2 variation among horses with differential TNFα baseline concentrations and response to intravenous lipopolysaccharide infusion.. Sci Rep 2023 Jan 27;13(1):1486.
                    doi: 10.1038/s41598-023-27956-ypubmed: 36707633google scholar: lookup
                  3. Minias P, Vinkler M. Selection Balancing at Innate Immune Genes: Adaptive Polymorphism Maintenance in Toll-Like Receptors.. Mol Biol Evol 2022 May 3;39(5).
                    doi: 10.1093/molbev/msac102pubmed: 35574644google scholar: lookup
                  4. Heine H, Adanitsch F, Peternelj TT, Haegman M, Kasper C, Ittig S, Beyaert R, Jerala R, Zamyatina A. Tailored Modulation of Cellular Pro-inflammatory Responses With Disaccharide Lipid A Mimetics.. Front Immunol 2021;12:631797.
                    doi: 10.3389/fimmu.2021.631797pubmed: 33815382google scholar: lookup
                  5. Atho'illah MF, Safitri YD, Nur'aini FD, Widyarti S, Tsuboi H, Rifa'i M. Elicited soybean extract attenuates proinflammatory cytokines expression by modulating TLR3/TLR4 activation in high-fat, high-fructose diet mice.. J Ayurveda Integr Med 2021 Jan-Mar;12(1):43-51.
                    doi: 10.1016/j.jaim.2021.01.003pubmed: 33531194google scholar: lookup
                  6. Loes AN, Hinman MN, Farnsworth DR, Miller AC, Guillemin K, Harms MJ. Identification and Characterization of Zebrafish Tlr4 Coreceptor Md-2.. J Immunol 2021 Mar 1;206(5):1046-1057.
                    doi: 10.4049/jimmunol.1901288pubmed: 33472906google scholar: lookup
                  7. Zamyatina A, Heine H. Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways.. Front Immunol 2020;11:585146.
                    doi: 10.3389/fimmu.2020.585146pubmed: 33329561google scholar: lookup
                  8. Arenas J, Pupo E, Phielix C, David D, Zariri A, Zamyatina A, Tommassen J, van der Ley P. Shortening the Lipid A Acyl Chains of Bordetella pertussis Enables Depletion of Lipopolysaccharide Endotoxic Activity.. Vaccines (Basel) 2020 Oct 9;8(4).
                    doi: 10.3390/vaccines8040594pubmed: 33050234google scholar: lookup
                  9. Romerio A, Peri F. Increasing the Chemical Variety of Small-Molecule-Based TLR4 Modulators: An Overview.. Front Immunol 2020;11:1210.
                    doi: 10.3389/fimmu.2020.01210pubmed: 32765484google scholar: lookup
                  10. Lozano-Aponte J, Scior T, Ambrosio FNM, González-Melchor M, Alexander C. Exploring electrostatic patterns of human, murine, equine and canine TLR4/MD-2 receptors.. Innate Immun 2020 Jul;26(5):364-380.
                    doi: 10.1177/1753425919894628pubmed: 31874581google scholar: lookup
                  11. Anderson JA, Loes AN, Waddell GL, Harms MJ. Tracing the evolution of novel features of human Toll-like receptor 4.. Protein Sci 2019 Jul;28(7):1350-1358.
                    doi: 10.1002/pro.3644pubmed: 31075178google scholar: lookup
                  12. Pizzuto M, Lonez C, Baroja-Mazo A, Martínez-Banaclocha H, Tourlomousis P, Gangloff M, Pelegrin P, Ruysschaert JM, Gay NJ, Bryant CE. Saturation of acyl chains converts cardiolipin from an antagonist to an activator of Toll-like receptor-4.. Cell Mol Life Sci 2019 Sep;76(18):3667-3678.
                    doi: 10.1007/s00018-019-03113-5pubmed: 31062071google scholar: lookup
                  13. Cochet F, Facchini FA, Zaffaroni L, Billod JM, Coelho H, Holgado A, Braun H, Beyaert R, Jerala R, Jimenez-Barbero J, Martin-Santamaria S, Peri F. Novel carboxylate-based glycolipids: TLR4 antagonism, MD-2 binding and self-assembly properties.. Sci Rep 2019 Jan 29;9(1):919.
                    doi: 10.1038/s41598-018-37421-wpubmed: 30696900google scholar: lookup
                  14. Velová H, Gutowska-Ding MW, Burt DW, Vinkler M. Toll-Like Receptor Evolution in Birds: Gene Duplication, Pseudogenization, and Diversifying Selection.. Mol Biol Evol 2018 Sep 1;35(9):2170-2184.
                    doi: 10.1093/molbev/msy119pubmed: 29893911google scholar: lookup
                  15. Loes AN, Bridgham JT, Harms MJ. Coevolution of the Toll-Like Receptor 4 Complex with Calgranulins and Lipopolysaccharide.. Front Immunol 2018;9:304.
                    doi: 10.3389/fimmu.2018.00304pubmed: 29515592google scholar: lookup
                  16. Pizzuto M, Gangloff M, Scherman D, Gay NJ, Escriou V, Ruysschaert JM, Lonez C. Toll-like receptor 2 promiscuity is responsible for the immunostimulatory activity of nucleic acid nanocarriers.. J Control Release 2017 Feb 10;247:182-193.
                    doi: 10.1016/j.jconrel.2016.12.029pubmed: 28040465google scholar: lookup
                  17. Billod JM, Lacetera A, Guzmán-Caldentey J, Martín-Santamaría S. Computational Approaches to Toll-Like Receptor 4 Modulation.. Molecules 2016 Jul 30;21(8).
                    doi: 10.3390/molecules21080994pubmed: 27483231google scholar: lookup
                  18. Liao K, Guo M, Niu F, Yang L, Callen SE, Buch S. Cocaine-mediated induction of microglial activation involves the ER stress-TLR2 axis.. J Neuroinflammation 2016 Feb 9;13:33.
                    doi: 10.1186/s12974-016-0501-2pubmed: 26860188google scholar: lookup
                  19. Günther J, Koy M, Berthold A, Schuberth HJ, Seyfert HM. Comparison of the pathogen species-specific immune response in udder derived cell types and their models.. Vet Res 2016 Feb 1;47:22.
                    doi: 10.1186/s13567-016-0307-3pubmed: 26830914google scholar: lookup
                  20. Vašl J, Oblak A, Peternelj TT, Klett J, Martín-Santamaría S, Gioannini TL, Weiss JP, Jerala R. Molecular Basis of the Functional Differences between Soluble Human Versus Murine MD-2: Role of Val135 in Transfer of Lipopolysaccharide from CD14 to MD-2.. J Immunol 2016 Mar 1;196(5):2309-18.
                    doi: 10.4049/jimmunol.1502074pubmed: 26826249google scholar: lookup
                  21. Paramo T, Tomasio SM, Irvine KL, Bryant CE, Bond PJ. Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response.. Sci Rep 2015 Dec 9;5:17997.
                    doi: 10.1038/srep17997pubmed: 26647780google scholar: lookup
                  22. Lonez C, Irvine KL, Pizzuto M, Schmidt BI, Gay NJ, Ruysschaert JM, Gangloff M, Bryant CE. Critical residues involved in Toll-like receptor 4 activation by cationic lipid nanocarriers are not located at the lipopolysaccharide-binding interface.. Cell Mol Life Sci 2015 Oct;72(20):3971-82.
                    doi: 10.1007/s00018-015-1915-1pubmed: 25956320google scholar: lookup
                  23. Mamat U, Wilke K, Bramhill D, Schromm AB, Lindner B, Kohl TA, Corchero JL, Villaverde A, Schaffer L, Head SR, Souvignier C, Meredith TC, Woodard RW. Detoxifying Escherichia coli for endotoxin-free production of recombinant proteins.. Microb Cell Fact 2015 Apr 16;14:57.
                    doi: 10.1186/s12934-015-0241-5pubmed: 25890161google scholar: lookup
                  24. Maeshima N, Evans-Atkinson T, Hajjar AM, Fernandez RC. Bordetella pertussis Lipid A Recognition by Toll-like Receptor 4 and MD-2 Is Dependent on Distinct Charged and Uncharged Interfaces.. J Biol Chem 2015 May 22;290(21):13440-53.
                    doi: 10.1074/jbc.M115.653881pubmed: 25837248google scholar: lookup
                  25. Bryant CE, Orr S, Ferguson B, Symmons MF, Boyle JP, Monie TP. International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease.. Pharmacol Rev 2015;67(2):462-504.
                    doi: 10.1124/pr.114.009928pubmed: 25829385google scholar: lookup
                  26. Vinkler M, Bainová H, Bryjová A, Tomášek O, Albrecht T, Bryja J. Characterisation of Toll-like receptors 4, 5 and 7 and their genetic variation in the grey partridge.. Genetica 2015 Feb;143(1):101-12.
                    doi: 10.1007/s10709-015-9819-4pubmed: 25626717google scholar: lookup
                  27. Anwar MA, Panneerselvam S, Shah M, Choi S. Insights into the species-specific TLR4 signaling mechanism in response to Rhodobacter sphaeroides lipid A detection.. Sci Rep 2015 Jan 7;5:7657.
                    doi: 10.1038/srep07657pubmed: 25563849google scholar: lookup
                  28. Vinkler M, Bainová H, Bryja J. Protein evolution of Toll-like receptors 4, 5 and 7 within Galloanserae birds.. Genet Sel Evol 2014 Nov 12;46(1):72.
                    doi: 10.1186/s12711-014-0072-6pubmed: 25387947google scholar: lookup
                  29. Hold GL, Berry S, Saunders KA, Drew J, Mayer C, Brookes H, Gay NJ, El-Omar EM, Bryant CE. The TLR4 D299G and T399I SNPs are constitutively active to up-regulate expression of Trif-dependent genes.. PLoS One 2014;9(11):e111460.
                    doi: 10.1371/journal.pone.0111460pubmed: 25365308google scholar: lookup
                  30. Oblak A, Jerala R. Species-specific activation of TLR4 by hypoacylated endotoxins governed by residues 82 and 122 of MD-2.. PLoS One 2014;9(9):e107520.
                    doi: 10.1371/journal.pone.0107520pubmed: 25203747google scholar: lookup
                  31. Liaunardy-Jopeace A, Bryant CE, Gay NJ. The COP II adaptor protein TMED7 is required to initiate and mediate the delivery of TLR4 to the plasma membrane.. Sci Signal 2014 Jul 29;7(336):ra70.
                    doi: 10.1126/scisignal.2005275pubmed: 25074978google scholar: lookup
                  32. Irvine KL, Gangloff M, Walsh CM, Spring DR, Gay NJ, Bryant CE. Identification of key residues that confer Rhodobacter sphaeroides LPS activity at horse TLR4/MD-2.. PLoS One 2014;9(5):e98776.
                    doi: 10.1371/journal.pone.0098776pubmed: 24879320google scholar: lookup
                  33. Shang L, Daubeuf B, Triantafilou M, Olden R, Dépis F, Raby AC, Herren S, Dos Santos A, Malinge P, Dunn-Siegrist I, Benmkaddem S, Geinoz A, Magistrelli G, Rousseau F, Buatois V, Salgado-Pires S, Reith W, Monteiro R, Pugin J, Leger O, Ferlin W, Kosco-Vilbois M, Triantafilou K, Elson G. Selective antibody intervention of Toll-like receptor 4 activation through Fc γ receptor tethering.. J Biol Chem 2014 May 30;289(22):15309-18.
                    doi: 10.1074/jbc.M113.537936pubmed: 24737331google scholar: lookup
                  34. Scior T, Lozano-Aponte J, Figueroa-Vazquez V, Yunes-Rojas JA, Zähringer U, Alexander C. Three-dimensional mapping of differential amino acids of human, murine, canine and equine TLR4/MD-2 receptor complexes conferring endotoxic activation by lipid A, antagonism by Eritoran and species-dependent activities of Lipid IVA in the mammalian LPS sensor system.. Comput Struct Biotechnol J 2013;7:e201305003.
                    doi: 10.5936/csbj.201305003pubmed: 24688739google scholar: lookup
                  35. Scior T, Alexander C, Zaehringer U. Reviewing and identifying amino acids of human, murine, canine and equine TLR4 / MD-2 receptor complexes conferring endotoxic innate immunity activation by LPS/lipid A, or antagonistic effects by Eritoran, in contrast to species-dependent modulation by lipid IVa.. Comput Struct Biotechnol J 2013;5:e201302012.
                    doi: 10.5936/csbj.201302012pubmed: 24688705google scholar: lookup
                  36. Metcalfe HJ, La Ragione RM, Smith DG, Werling D. Functional characterisation of bovine TLR5 indicates species-specific recognition of flagellin.. Vet Immunol Immunopathol 2014 Feb 15;157(3-4):197-205.
                    doi: 10.1016/j.vetimm.2013.12.006pubmed: 24461722google scholar: lookup
                  37. Paramo T, Piggot TJ, Bryant CE, Bond PJ. The structural basis for endotoxin-induced allosteric regulation of the Toll-like receptor 4 (TLR4) innate immune receptor.. J Biol Chem 2013 Dec 20;288(51):36215-25.
                    doi: 10.1074/jbc.M113.501957pubmed: 24178299google scholar: lookup
                  38. Martín-Martín I, Molina R, Jiménez M. Molecular and immunogenic properties of apyrase SP01B and D7-related SP04 recombinant salivary proteins of Phlebotomus perniciosus from Madrid, Spain.. Biomed Res Int 2013;2013:526069.
                    doi: 10.1155/2013/526069pubmed: 24171166google scholar: lookup
                  39. Fornůsková A, Vinkler M, Pagès M, Galan M, Jousselin E, Cerqueira F, Morand S, Charbonnel N, Bryja J, Cosson JF. Contrasted evolutionary histories of two Toll-like receptors (Tlr4 and Tlr7) in wild rodents (MURINAE).. BMC Evol Biol 2013 Sep 12;13:194.
                    doi: 10.1186/1471-2148-13-194pubmed: 24028551google scholar: lookup
                  40. Artner D, Oblak A, Ittig S, Garate JA, Horvat S, Arrieumerlou C, Hofinger A, Oostenbrink C, Jerala R, Kosma P, Zamyatina A. Conformationally constrained lipid A mimetics for exploration of structural basis of TLR4/MD-2 activation by lipopolysaccharide.. ACS Chem Biol 2013 Nov 15;8(11):2423-32.
                    doi: 10.1021/cb4003199pubmed: 23952219google scholar: lookup
                  41. Herre J, Grönlund H, Brooks H, Hopkins L, Waggoner L, Murton B, Gangloff M, Opaleye O, Chilvers ER, Fitzgerald K, Gay N, Monie T, Bryant C. Allergens as immunomodulatory proteins: the cat dander protein Fel d 1 enhances TLR activation by lipid ligands.. J Immunol 2013 Aug 15;191(4):1529-35.
                    doi: 10.4049/jimmunol.1300284pubmed: 23878318google scholar: lookup
                  42. Irvine KL, Hopkins LJ, Gangloff M, Bryant CE. The molecular basis for recognition of bacterial ligands at equine TLR2, TLR1 and TLR6.. Vet Res 2013 Jul 4;44(1):50.
                    doi: 10.1186/1297-9716-44-50pubmed: 23826682google scholar: lookup
                  43. Chan M, Hayashi T, Mathewson RD, Nour A, Hayashi Y, Yao S, Tawatao RI, Crain B, Tsigelny IF, Kouznetsova VL, Messer K, Pu M, Corr M, Carson DA, Cottam HB. Identification of substituted pyrimido[5,4-b]indoles as selective Toll-like receptor 4 ligands.. J Med Chem 2013 Jun 13;56(11):4206-23.
                    doi: 10.1021/jm301694xpubmed: 23656327google scholar: lookup
                  44. Maeshima N, Fernandez RC. Recognition of lipid A variants by the TLR4-MD-2 receptor complex.. Front Cell Infect Microbiol 2013;3:3.
                    doi: 10.3389/fcimb.2013.00003pubmed: 23408095google scholar: lookup
                  45. Gustot A, Raussens V, Dehousse M, Dumoulin M, Bryant CE, Ruysschaert JM, Lonez C. Activation of innate immunity by lysozyme fibrils is critically dependent on cross-β sheet structure.. Cell Mol Life Sci 2013 Aug;70(16):2999-3012.
                    doi: 10.1007/s00018-012-1245-5pubmed: 23334185google scholar: lookup
                  46. Bryant CE, Monie TP. Mice, men and the relatives: cross-species studies underpin innate immunity.. Open Biol 2012 Apr;2(4):120015.
                    doi: 10.1098/rsob.120015pubmed: 22724060google scholar: lookup
                  47. Werners AH, Bryant CE. Pattern recognition receptors in equine endotoxaemia and sepsis.. Equine Vet J 2012 Jul;44(4):490-8.
                    doi: 10.1111/j.2042-3306.2012.00574.xpubmed: 22607193google scholar: lookup
                  48. Ohto U, Fukase K, Miyake K, Shimizu T. Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2.. Proc Natl Acad Sci U S A 2012 May 8;109(19):7421-6.
                    doi: 10.1073/pnas.1201193109pubmed: 22532668google scholar: lookup
                  49. Dunn-Siegrist I, Tissières P, Drifte G, Bauer J, Moutel S, Pugin J. Toll-like receptor activation of human cells by synthetic triacylated lipid A-like molecules.. J Biol Chem 2012 May 11;287(20):16121-31.
                    doi: 10.1074/jbc.M112.348383pubmed: 22433865google scholar: lookup
                  50. Yu L, Phillips RL, Zhang D, Teghanemt A, Weiss JP, Gioannini TL. NMR studies of hexaacylated endotoxin bound to wild-type and F126A mutant MD-2 and MD-2·TLR4 ectodomain complexes.. J Biol Chem 2012 May 11;287(20):16346-55.
                    doi: 10.1074/jbc.M112.343467pubmed: 22433852google scholar: lookup
                  51. Bowen WS, Minns LA, Johnson DA, Mitchell TC, Hutton MM, Evans JT. Selective TRIF-dependent signaling by a synthetic toll-like receptor 4 agonist.. Sci Signal 2012 Feb 14;5(211):ra13.
                    doi: 10.1126/scisignal.2001963pubmed: 22337809google scholar: lookup
                  52. Gangloff M. Different dimerisation mode for TLR4 upon endosomal acidification?. Trends Biochem Sci 2012 Mar;37(3):92-8.
                    doi: 10.1016/j.tibs.2011.11.003pubmed: 22196451google scholar: lookup
                  53. Piazza M, Calabrese V, Damore G, Cighetti R, Gioannini T, Weiss J, Peri F. A synthetic lipid A mimetic modulates human TLR4 activity.. ChemMedChem 2012 Feb 6;7(2):213-7.
                    doi: 10.1002/cmdc.201100494pubmed: 22140087google scholar: lookup
                  54. DeMarco ML, Woods RJ. From agonist to antagonist: structure and dynamics of innate immune glycoprotein MD-2 upon recognition of variably acylated bacterial endotoxins.. Mol Immunol 2011 Oct;49(1-2):124-33.
                    doi: 10.1016/j.molimm.2011.08.003pubmed: 21924775google scholar: lookup
                  55. Manavalan B, Basith S, Choi S. Similar Structures but Different Roles - An Updated Perspective on TLR Structures.. Front Physiol 2011;2:41.
                    doi: 10.3389/fphys.2011.00041pubmed: 21845181google scholar: lookup
                  56. Coler RN, Bertholet S, Moutaftsi M, Guderian JA, Windish HP, Baldwin SL, Laughlin EM, Duthie MS, Fox CB, Carter D, Friede M, Vedvick TS, Reed SG. Development and characterization of synthetic glucopyranosyl lipid adjuvant system as a vaccine adjuvant.. PLoS One 2011 Jan 26;6(1):e16333.
                    doi: 10.1371/journal.pone.0016333pubmed: 21298114google scholar: lookup
                  57. Mengwasser KE, Bryant CE, Gay NJ, Gangloff M. LPS ligand and culture additives improve production of monomeric MD-1 and 2 in Pichia pastoris by decreasing aggregation and intermolecular disulfide bonding.. Protein Expr Purif 2011 Apr;76(2):173-83.
                    doi: 10.1016/j.pep.2010.11.018pubmed: 21130168google scholar: lookup
                  58. Liu M, John CM, Jarvis GA. Phosphoryl moieties of lipid A from Neisseria meningitidis and N. gonorrhoeae lipooligosaccharides play an important role in activation of both MyD88- and TRIF-dependent TLR4-MD-2 signaling pathways.. J Immunol 2010 Dec 1;185(11):6974-84.
                    doi: 10.4049/jimmunol.1000953pubmed: 21037101google scholar: lookup
                  59. Goodall JC, Wu C, Zhang Y, McNeill L, Ellis L, Saudek V, Gaston JS. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression.. Proc Natl Acad Sci U S A 2010 Oct 12;107(41):17698-703.
                    doi: 10.1073/pnas.1011736107pubmed: 20876114google scholar: lookup
                  60. Meng J, Drolet JR, Monks BG, Golenbock DT. MD-2 residues tyrosine 42, arginine 69, aspartic acid 122, and leucine 125 provide species specificity for lipid IVA.. J Biol Chem 2010 Sep 3;285(36):27935-43.
                    doi: 10.1074/jbc.M110.134668pubmed: 20592019google scholar: lookup
                  61. Meng J, Lien E, Golenbock DT. MD-2-mediated ionic interactions between lipid A and TLR4 are essential for receptor activation.. J Biol Chem 2010 Mar 19;285(12):8695-702.
                    doi: 10.1074/jbc.M109.075127pubmed: 20018893google scholar: lookup
                  62. Bryant CE, Spring DR, Gangloff M, Gay NJ. The molecular basis of the host response to lipopolysaccharide.. Nat Rev Microbiol 2010 Jan;8(1):8-14.
                    doi: 10.1038/nrmicro2266pubmed: 19946286google scholar: lookup
                  63. Vasl J, Oblak A, Gioannini TL, Weiss JP, Jerala R. Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2.. J Immunol 2009 Oct 15;183(8):5138-45.
                    doi: 10.4049/jimmunol.0901544pubmed: 19783674google scholar: lookup
                  64. Doz E, Rose S, Court N, Front S, Vasseur V, Charron S, Gilleron M, Puzo G, Fremaux I, Delneste Y, Erard F, Ryffel B, Martin OR, Quesniaux VF. Mycobacterial phosphatidylinositol mannosides negatively regulate host Toll-like receptor 4, MyD88-dependent proinflammatory cytokines, and TRIF-dependent co-stimulatory molecule expression.. J Biol Chem 2009 Aug 28;284(35):23187-96.
                    doi: 10.1074/jbc.M109.037846pubmed: 19561082google scholar: lookup
                  65. O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer.. Pharmacol Rev 2009 Jun;61(2):177-97.
                    doi: 10.1124/pr.109.001073pubmed: 19474110google scholar: lookup
                  66. Resman N, Vasl J, Oblak A, Pristovsek P, Gioannini TL, Weiss JP, Jerala R. Essential roles of hydrophobic residues in both MD-2 and toll-like receptor 4 in activation by endotoxin.. J Biol Chem 2009 May 29;284(22):15052-60.
                    doi: 10.1074/jbc.M901429200pubmed: 19321453google scholar: lookup
                  67. Park BS, Song DH, Kim HM, Choi BS, Lee H, Lee JO. The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.. Nature 2009 Apr 30;458(7242):1191-5.
                    doi: 10.1038/nature07830pubmed: 19252480google scholar: lookup
                  Subscribe to our newsletter
                  Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.