Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling.
Myeloid differentiating factor 88 (MyD88) and MyD88 adaptor-like (Mal) are adaptor molecules critically involved in the Toll-like receptor (TLR) 4 signaling pathway. While Mal has been proposed to serve as a membrane-sorting adaptor, MyD88 mediates signal transduction from activated TLR4 to downstream components. The Toll/Interleukin-1 receptor (TIR) domain of MyD88 is responsible for sorting and signaling via direct or indirect TIR-TIR interactions between Mal and TLR4. However, the molecular mechanisms involved in multiple interactions of the TIR domain remain unclear. The present study describes the solution structure of the MyD88 TIR domain. Reporter gene assays revealed that 3 discrete surface sites in the TIR domain of MyD88 are important for TLR4 signaling. Two of these sites were shown to mediate direct binding to the TIR domain of Mal. Interestingly, Mal-TIR, but not MyD88-TIR, directly binds to the cytosolic TIR domain of TLR4. These observations suggested that the heteromeric assembly of TIR domains of the receptor and adaptors constitutes the initial step of TLR4 intracellular signal transduction.
Ohnishi
Hidenori
H
Department of Pediatrics, Graduate School of Medicine, Center for Emerging Infectious Diseases, and Center for Advanced Drug Research, Gifu University, Gifu, Japan.
Tochio
Hidehito
H
Kato
Zenichiro
Z
Orii
Kenji E
KE
Li
Ailian
A
Kimura
Takeshi
T
Hiroaki
Hidekazu
H
Kondo
Naomi
N
Shirakawa
Masahiro
M
D001665:Binding Sites; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4