Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA

Liu, Lin; Botos, Istvan; Wang, Yan; Leonard, Joshua N.; Shiloach, Joseph; Segal, David M.; Davies, David R.

doi:10.1126/science.1155406

Cited by 639 publications

(643 citation statements)

References 15 publications

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“…The biological relevance of the contact surfaces determined for the trimeric structure of TLR3-TM is supported by the model of the full-length TLR3 receptor in the active state, constructed on the basis of crystal structures of dimeric ECD and TIR domain in the group of prof. Davies [4]. In this model TM helix has the same disposition as was found in the present work -it starts at Phe 702 and ends at Phe 725 .…”

Section: Discussionsupporting

confidence: 57%

“…Moreover, a computer model of the dimeric full-length TLR3 receptor in the active state was build [4]. Nevertheless, the role of the transmembrane domain (TMD) in TLR signaling is still elusive, while its significance for the TLR activation was demonstrated in recent studies.…”

Section: Introductionmentioning

confidence: 99%

“…TLRs belong to the type I transmembrane proteins and consist of the extracellular ligand-binding domain extracellular domain (ECD), single transmembrane a-helix and intracellular Toll-interleukin I receptor domain (TIR), which is responsible for the downstream signaling [1,2]. According to crystal structures, TLRs form homo-or heterodimeric signaling complexes interacting with the single PAMP molecule [3][4][5][6][7]. The medical and biological significance of toll-like receptor (TLR) signaling is obvious, since the disregulation of the TLR system may cause various autoimmune diseases and septic shock [8][9][10][11], and some therapeutic strategies targeting TLRs have already emerged [8,11,12].…”

Section: Introductionmentioning

confidence: 99%

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Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

2014

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Edited by Christian Griesinger Keyword:Toll-like receptor Transmembrane domain Spatial structure Dimerization Free energy a b s t r a c t Toll-like receptors (TLRs) take part in both the innate and adaptive immune systems. The role of the transmembrane domain in TLR signaling is still elusive, while its importance for the TLR activation was clearly demonstrated. In the present study the ability of the TLR3 transmembrane domain to form dimers and trimers in detergent micelles was shown by solution NMR spectroscopy. Spatial structures and free energy magnitudes were determined for the TLR3 transmembrane domain in dimeric and trimeric states, and two possible surfaces that may be used for the helix-helix interaction by the full-length TLR3 were revealed. Structured summary of protein interactions:TLR3-TM and TLR3-TM bind by nuclear magnetic resonance (1, 2)

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Section: Discussionsupporting

confidence: 57%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

2014

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“…7). 130 A synthetic analog of naturally occurring dsRNA, as 1997 indicated that PAM 3 CSK 4 markedly enhanced the humoral response to haptens conjugated to poly-L-lysine; adjuvanticity was also observed by these authors for the lipopeptide-T H 1 cell epitope conjugates in in vitro immunization protocols. 105 It was subsequently shown using human lymphocytes ex vivo, that PAM 3 CSK 4 -dependent CD4 + T cell differentiation and proliferation required professional APC, and that naïve CD4 + T cell differentiation progressed with faster kinetics in the presence of the adjuvant.…”

Section: Intracellular Tlr3 Activation: Dsrna and Poly (I:c)mentioning

confidence: 96%

Potential adjuvantic properties of innate immune stimuli

et al. 2009

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Just as the prescient comment by Gaston Ramon was relegated to the last footnote of his 1926 paper, 1 so has research on the mechanisms of action of adjuvants, until recently, languished as parenthetical annotations and addenda in the archives of immunology and vaccine development. Ramon defined immunological adjuvants as "substances used in combination with a specific antigen that produced a more robust immune response than the antigen alone." Interestingly enough, he was referring to his empirical findings that the addition of bread crumbs, tapioca, saponin and 'starch oil' to antigenic preparations greatly enhanced antibody responses to diphtheria or tetanus. 2 A year later, the adjuvanticity of aluminum salts (primarily phosphate and hydroxide) was discovered by Glenny and coworkers. 3 In the 83 years that have elapsed, the repertoire of investigational adjuvants has grown to encompass a very wide range of materials, 4 but aluminum salt-based mineral salts (generically, and incorrectly, termed "alum") have remained the only adjuvants currently approved by the FDA. Aluminum salts have enjoyed a good safety record, but they are weak adjuvants for antibody induction and induce a T helper-2 (T H 2)-skewed, rather than a T helper-1 (T H 1) response. 5,6 Furthermore, not only are aluminum salts ineffective at inducing cytotoxic T lymphocyte (CTL) or mucosal IgA antibody responses, but also have a propensity to induce IgE responses, which have been associated with allergic reactions in some subjects. 5,6 Very recent reports implicate the Nalp3 inflammasome, a component of the innate immune response, as the effector limb of alum-associated adjuvanticity. [7][8][9] In 1962, Dresser observed that injection of purified soluble proteins not only failed to stimulate an immune response, but tolerized animals unless a bacterial extract was admixed with the protein immunogen. 10 This led him to redefine adjuvanticity as "a property of a substance which can act as a physiological switch, directing at least some immunologically competent cells to respond by making antibody rather than by becoming immunologically paralyzed by the antigen," 11 confirming Johnson's earlier observations that lipopolysaccharide (LPS) from Gram-negative bacteria exerted potent adjuvant properties, 12 and perhaps paved the way for the subsequent discovery of the wide range of microorganism-derived adjuvants. 13 TLRs are pattern recognition receptors present on diverse cell types that recognize specific molecular patterns present in molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). 14,15 There are 10 TLRs in the human genome;

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“…On the other hand, a wide variety of RNA species or analogues have also been reported to be immunogenic including ssRNA and dsRNA [20]. The investigation of the immune-compatibly represents one of the most important features for their translation to the clinic.…”

Section: Introductionmentioning

confidence: 99%

Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

Osman

Kaneko

Carini

et al. 2018

Expert Opinion on Drug Delivery

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Introduction: Macromolecules with unique effects and potency are increasingly being considered for application in lung pathologies. Numerous delivery strategies for these macromolecules through the lung have been investigated to improve the targeting and overall efficacy.Areas covered: Targeting approaches from delivery devices, formulation strategies and specific targets are discussed.Expert opinion: Although macromolecules are a heterogeneous group of molecules, a number of strategies have been investigated at the macro, micro, and nanoscopic scale for the delivery of macromolecules to specific sites and cells of lung tissues. Targeted approaches are already in use at the macroscopic scale through inhalation devices and formulations, but targeting strategies at the micro and nanoscopic scale are still in the laboratory stage. The combination of controlling lung deposition and targeting after deposition, through a combination of targeting strategies could be the future direction for the treatment of lung pathologies through the pulmonary route.

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Structural Basis of Toll-Like Receptor 3 Signaling with Double-Stranded RNA

Cited by 639 publications

References 15 publications

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

Toll‐like receptor 3 transmembrane domain is able to perform various homotypic interactions: An NMR structural study

Potential adjuvantic properties of innate immune stimuli

Carriers for the targeted delivery of aerosolized macromolecules for pulmonary pathologies

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