Details of Toll-like receptor : adapter interaction revealed by germ-line mutagenesis

作者：Jiang Zhengfan; Georgel Philippe; Li Chenglong; Choe Jungwoo; Crozat Karine; Rutschmann Sophie; Du Xin; Bigby Tim; Mudd Suzanne; Sovath Sosathya; Wilson Ian A; Olson Arthur; Beutler Bruce^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2006, 103(29): 10961-10966.

DOI：10.1073/pnas.0603804103

• genetics
• MyD88
• positional cloning
• signaling

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.

• 出版日期2006-7-18