Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis.
The immunovariant N-ethyl-N-nitrosourea-induced mutations Pococurante (Poc) and Lackadaisical were found to alter MyD88, creating striking receptor-selective effects. Poc, in particular, prevented sensing of all MyD88-dependent Toll-like receptor (TLR) ligands except diacyl lipopeptides. Furthermore, Poc-site and classical BB loop mutations caused equivalent phenotypes when engrafted into any TLR/IL-1 receptor/resistance (TIR) domain. These observations, complemented by data from docking studies and site-directed mutagenesis, revealed that BB loops and Poc sites interact homotypically across the receptor:adapter signaling interface, whereas the C-terminal alpha(E)-helices support adapter:adapter and receptor:receptor oligomerization. We have thus defined the TIR domain surface that mediates association between TLRs and MyD88 and the surface required for MyD88 or TLR oligomerization. Moreover, MyD88 engages individual TLRs differently, suggesting the feasibility of selective pharmacologic TIR domain receptor blockade.
Jiang
Zhengfan
Z
Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Georgel
Philippe
P
Li
Chenglong
C
Choe
Jungwoo
J
Crozat
Karine
K
Rutschmann
Sophie
S
Du
Xin
X
Bigby
Tim
T
Mudd
Suzanne
S
Sovath
Sosathya
S
Wilson
Ian A
IA
Olson
Arthur
A
Beutler
Bruce
B
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis / Q000235:genetics*; D053594:Myeloid Differentiation Factor 88; D010641:Phenotype; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D008074:Lipoproteins; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors