HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 46, 47431-47437, November 12, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/46/47431    most recent M408724200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujimoto, T. Articles by Muta, T. Search for Related Content PubMed PubMed Citation Articles by Fujimoto, T. Articles by Muta, T. Social Bookmarking                      What's this?

The Amino-terminal Region of Toll-like Receptor 4 Is Essential for Binding to MD-2 and Receptor Translocation to the Cell Surface^*

Takeshi Fujimoto, Soh Yamazaki, Akiko Eto-Kimura, Koichiro Takeshige, and Tatsushi Muta¶

From the Department of Molecular and Cellular Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582 and Host and Defense, Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Toll-like receptor 4 (TLR4) and MD-2 are pivotal components that elicit inflammatory responses to lipopolysaccharide (LPS). They have been shown to form a physical complex on the cell surface that responds directly to LPS. However, the functional region of TLR4 required for association with MD-2 and LPS responsiveness is poorly understood. To identify the region of TLR4, we created a series of mutants with deletions in the extracellular domain and examined their activities in human embryonic kidney 293 cells. A mutant with a 317-amino acid deletion from the membrane proximal region of TLR4 was capable of associating with MD-2, while only a 9-amino acid truncation of the N terminus severely impaired the interaction. The association between the two molecules was well correlated with TLR4 maturation into an endoglycosidase H-resistant form and the cell surface expression. Mouse MD-2 bound to human TLR4, but its activity to facilitate the cell surface expression of TLR4 and confer LPS responsiveness was much weaker than that of human MD-2, indicating species specificity. A chimeric receptor composed of the N-terminal region of human TLR4 and the adjacent region of mouse TLR4 showed preference for human MD-2 in its transport to the cell surface and responsiveness to LPS. Taken together, the N-terminal region of TLR4 is essential for association with MD-2, which is required for the cell surface expression and hence the responsiveness to LPS.

Received for publication, July 30, 2004 , and in revised form, August 25, 2004.

^* This study was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan (to T. M., K. T., and S. Y.) and grants from the Naito Foundation (to T. M.), the Kaibara Foundation (to T. M.), and the Kao Foundation (to S. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 81-92-642-6103; Fax: 81-92-642-6103; E-mail: tmuta{at}mailserver.med.kyushu-u.ac.jp.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. A. Awomoyi, P. Rallabhandi, T. I. Pollin, E. Lorenz, M. B. Sztein, M. S. Boukhvalova, V. G. Hemming, J. C. G. Blanco, and S. N. Vogel Association of TLR4 Polymorphisms with Symptomatic Respiratory Syncytial Virus Infection in High-Risk Infants and Young Children J. Immunol., September 1, 2007; 179(5): 3171 - 3177. [Abstract] [Full Text] [PDF]

				C. Nishitani, H. Mitsuzawa, H. Sano, T. Shimizu, N. Matsushima, and Y. Kuroki Toll-like Receptor 4 Region Glu24-Lys47 Is a Site for MD-2 Binding: IMPORTANCE OF CYS29 AND CYS40 J. Biol. Chem., December 15, 2006; 281(50): 38322 - 38329. [Abstract] [Full Text] [PDF]

				H. Mitsuzawa, C. Nishitani, N. Hyakushima, T. Shimizu, H. Sano, N. Matsushima, K. Fukase, and Y. Kuroki Recombinant Soluble Forms of Extracellular TLR4 Domain and MD-2 Inhibit Lipopolysaccharide Binding on Cell Surface and Dampen Lipopolysaccharide-Induced Pulmonary Inflammation in Mice J. Immunol., December 1, 2006; 177(11): 8133 - 8139. [Abstract] [Full Text] [PDF]

				R. M Gorczynski, Y. Kai, and K. Miyake MD1 Expression Regulates Development of Regulatory T Cells J. Immunol., July 15, 2006; 177(2): 1078 - 1084. [Abstract] [Full Text] [PDF]

				S. R. Coats, T.-T. T. Pham, B. W. Bainbridge, R. A. Reife, and R. P. Darveau MD-2 Mediates the Ability of Tetra-Acylated and Penta-Acylated Lipopolysaccharides to Antagonize Escherichia coli Lipopolysaccharide at the TLR4 Signaling Complex J. Immunol., October 1, 2005; 175(7): 4490 - 4498. [Abstract] [Full Text] [PDF]

				K. Brandl, T. Gluck, P. Hartmann, B. Salzberger, and W. Falk A designed TLR4/MD-2 complex to capture LPS Innate Immunity, August 1, 2005; 11(4): 197 - 206. [Abstract] [PDF]