Document Detail


An alanine-to-proline mutation in the BB-loop of TLR3 Toll/IL-1R domain switches signalling adaptor specificity from TRIF to MyD88.
MedLine Citation:
PMID:  24198284     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A functionally important proline residue is highly conserved in the cytosolic Toll/IL-1R signaling domains of human TLRs. The antiviral Toll, TLR3, is unusual because it has alanine instead of proline at this position and is the only human TLR that associates directly with the adaptor molecule TIR domain-containing adaptor inducing IFN-β (TRIF) rather than MyD88. In this article, we report that a mutant TLR3 that substitutes the BB-loop alanine for proline (A795P) enhances NF-κB activation but is incapable of mediating TRIF-dependent IFN response factor 3 responses. Wild-type and A795P TLR3 associate constitutively with both TRIF and MyD88, and activation induces additional binding of TRIF to the wild-type and of MyD88 to the A795P mutant receptors, respectively. In addition, activation of A795P, but not wild-type TLR3, leads to the recruitment of TRAF6, a downstream signal transducer of the MyD88-dependent pathway. These results show that adaptor specificity can be conferred by minimal determinants of the Toll/IL-1R domain.
Authors:
Brett Verstak; Christopher J Arnot; Nicholas J Gay
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-11-06
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  191     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2013 Dec 
Date Detail:
Created Date:  2013-12-09     Completed Date:  2014-02-18     Revised Date:  2014-06-17    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6101-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Vesicular Transport / antagonists & inhibitors,  physiology
Alanine / chemistry
Amino Acid Substitution*
Binding Sites
HEK293 Cells
Humans
Interferon Regulatory Factor-3 / physiology
Mutation, Missense*
Myeloid Differentiation Factor 88 / metabolism
NF-kappa B / physiology
Point Mutation*
Poly I-C / pharmacology
Proline / chemistry
Protein Binding
Protein Structure, Tertiary
Recombinant Fusion Proteins / metabolism
Signal Transduction / genetics
Species Specificity
Structure-Activity Relationship
TNF Receptor-Associated Factor 6 / metabolism
Toll-Like Receptor 3 / chemistry,  genetics*,  physiology
Grant Support
ID/Acronym/Agency:
081744//Wellcome Trust; 100321//Wellcome Trust; G1000133//Medical Research Council; G1000133-E01//Medical Research Council
Chemical
Reg. No./Substance:
0/Adaptor Proteins, Vesicular Transport; 0/Interferon Regulatory Factor-3; 0/Irf3 protein, mouse; 0/MYD88 protein, human; 0/Myeloid Differentiation Factor 88; 0/NF-kappa B; 0/Recombinant Fusion Proteins; 0/TICAM1 protein, human; 0/TLR3 protein, human; 0/TNF Receptor-Associated Factor 6; 0/Toll-Like Receptor 3; 24939-03-5/Poly I-C; 9DLQ4CIU6V/Proline; OF5P57N2ZX/Alanine
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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