title: Differential adapter recruitment by TLR2 co-receptors.
abstract: TLR2 heterodimers with TLR1 or TLR6 recognize distinct pathogen-associated molecules such as tri- and di-acylated lipopeptides. The activated TLR2 heterodimers recruit Toll-IL-1R domain- (TIR-) containing adapter proteins, TIRAP and MyD88, through the receptor TIR domains. Molecular recognition mechanisms responsible for agonist-driven, TIR domain-mediated receptor-adapter interactions as well as the structure of resultant signaling complexes remain unknown. We previously reported that the cell-permeable peptide derived from helix D of TLR2 TIR (2R9) specifically binds TIRAP in vitro and in cells and thereby inhibits TIRAP-dependent TLR signaling. This study demonstrates that cell-permeable peptides from D helix of TLR1 or TLR6, peptides 1R9 and 6R9 respectively, inhibit signaling mediated by cognate TLR2 co-receptors. Interestingly, 1R9 and 6R9 bind different TLR2 adapters, as they selectively bind MyD88 and TIRAP TIR, respectively. Both peptides block the agonist-induced co-immunoprecipitation (co-IP) of TLR2 with TIRAP or MyD88, but not TLR2 co-IP with co-receptors. Our data suggest that D helices of TLR1 and TLR6 TIR domains are adapter recruitment sites in both co-receptors; yet the sites recruit different adapters. The D helix in TLR1 is the MyD88 docking site, whereas in TLR6 this site recruits TIRAP.
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore St., HSFI, Baltimore, MD 21201, USA.
authors.forename: Wenji
authors.initials: W
authors.lastname: Piao
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore St., HSFI, Baltimore, MD 21201, USA.
authors.forename: Lisa W
authors.initials: LW
authors.lastname: Ru
authors.affiliation: Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore St., HSFI, Baltimore, MD 21201, USA vtoshchakov@som.umaryland.edu.
authors.forename: Vladimir Y
authors.initials: VY
authors.lastname: Toshchakov
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000378:metabolism*; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D055503:Protein Multimerization; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008024:Ligands; D010446:Peptide Fragments; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6
keywords: MyD88; TIR domain; TIRAP; TLR1; TLR2; TLR6