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

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

doi:10.1073/pnas.0603804103

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

Zhengfan Jiang, Philippe Georgel, Chenglong Li, Jungwoo Choe, Karine Crozat, Sophie Rutschmann, Xin Du, Tim Bigby, Suzanne Mudd, Sosathya Sovath, Ian A. Wilson, Arthur Olson, Bruce Beutler

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113 Scopus citations

Abstract

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 α_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.

Original language	English (US)
Pages (from-to)	10961-10966
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	103
Issue number	29
DOIs	https://doi.org/10.1073/pnas.0603804103
State	Published - Jul 18 2006

Keywords

Genetics
MyD88
Positional cloning
Signaling

ASJC Scopus subject areas

General

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10.1073/pnas.0603804103

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Jiang, Z., Georgel, P., Li, C., Choe, J., Crozat, K., Rutschmann, S., Du, X., Bigby, T., Mudd, S., Sovath, S., Wilson, I. A., Olson, A., & Beutler, B. (2006). Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis. Proceedings of the National Academy of Sciences of the United States of America, 103(29), 10961-10966. https://doi.org/10.1073/pnas.0603804103

Jiang, Z, Georgel, P, Li, C, Choe, J, Crozat, K, Rutschmann, S, Du, X, Bigby, T, Mudd, S, Sovath, S, Wilson, IA, Olson, A & Beutler, B 2006, 'Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 29, pp. 10961-10966. https://doi.org/10.1073/pnas.0603804103

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abstract = "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 αE-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.",

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AU - Du, Xin

AU - Bigby, Tim

AU - Mudd, Suzanne

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AU - Wilson, Ian A.

AU - Olson, Arthur

AU - Beutler, Bruce

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

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