Breakthrough with TIR Domain Interaction in the Production of Type I Interferons

Research Press Release | January 08, 2014

Press Release
Key Points

-Interactive surface between TICAM-1 and TICAM-2 identified through explication of TIR domains in TICAM-1 and TICAM-2.

-TICAM-1 found to bind with the surface created by the formation of TICAM-2 homodimers.

-Downstream TIR domain binding found to require upstream TIR domain dimer formation, indicating the possibility that the formation of massive complexes mediated by the TIR domain may efficiently transmit the TLR downstream signal.


Overview

Our bodies register the invasion of pathogens by detecting the molecules characteristic of those bacteria and viruses, and eradicate them. This mechanism is known as innate immunity. Toll-like receptors (TLR) on the cell surface detect molecules characteristic of pathogens, the Toll/interleukin-1 receptor (TIR) domain of the TLR then interacts with the TIR domain of adaptor molecules, activating a downstream signal pathway, leading to the production of proinflammatory cytokines and interferons.


We used NMR to elucidate the solution structure of the TIR domain of the TLR4 downstream adaptor molecules, TICAM-1 and TICAM-2, connected with the production of type I interferon. We also identified the mechanism by which the homo- and heterodimers are formed, using a combination of structural information and mutation experiment based on the yeast two-hybrid screening.


The result was the identification of downstream TIR domain binding to the surface created by the dimerization of the upstream TIR domain. Signal transmission was found to require upstream TIR domain dimer formation, indicating the possibility that massive complexes bridged by the TICAM-2 and TICAM-1 TIR domains formed in the TLR4 downstream may efficiently transmit signals.

Inquiries

Fuyuhiko Inagaki, Specially Appointed Professor, Faculty of Advanced Life Science, Hokkaido University

TEL:+81-11-706-9011

FAX:+81-11-706-9012

E-mail: finagaki@pharm.hokudai.ac.jp

Japanese

Link

I 型インターフェロン産生にかかわる TIRドメイン間の相互作用を初めて解明
Publications  Proceedings of the National Academy of Sciences of the United States of America (2013.11.19)

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