Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

doi:10.1073/pnas.0812956106

Structural basis for the multiple interactions of the MyD88 TIR domain in TLR4 signaling

^aDepartment of Pediatrics, Graduate School of Medicine,
^cCenter for Emerging Infectious Diseases, and
^dCenter for Advanced Drug Research, Gifu University, Gifu, 501-1194, Japan;
^bDepartment of Molecular Engineering, Graduate School of Engineering, Kyoto University, Kyoto, 615-8510, Japan;
^eDivision of Structural Biology, Graduate School of Medicine, Kobe University, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan; and
^fCore Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Hon-cho 4-1-8, Kawaguchi, Saitama, 332-0012, Japan

Edited by Jack L. Strominger, Harvard University, Cambridge, MA, and approved April 29, 2009 (received for review December 19, 2008)

Abstract

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.

Footnotes

¹To whom correspondence may be addressed. E-mail: tochio{at}moleng.kyoto-u.ac.jp or zen-k{at}gifu-u.ac.jp
Author contributions: H.O., H.T., Z.K., N.K., and M.S. designed research; H.O., H.T., Z.K., K.E.O., A.L., T.K., and H.H. performed research; H.O., H.T., Z.K., and M.S. analyzed data; and H.O., H.T., Z.K., and M.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2Z5V).
This article contains supporting information online at www.pnas.org/cgi/content/full/0812956106/DCSupplemental.
Freely available online through the PNAS open access option.