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

J. Biol. Chem., Vol. 280, Issue 28, 26152-26159, July 15, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/28/26152    most recent M503262200v1 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 Li, C. Articles by Hawiger, J. Search for Related Content PubMed PubMed Citation Articles by Li, C. Articles by Hawiger, J. Social Bookmarking                      What's this?

Interactive Sites in the MyD88 Toll/Interleukin (IL) 1 Receptor Domain Responsible for Coupling to the IL1 Signaling Pathway^*

Chunsheng Li, Jozef Zienkiewicz, and Jacek Hawiger

From the Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232

Myeloid differentiation factor MyD88 is the essential adaptor protein that integrates and transduces intracellular signals generated by multiple Toll-like receptors including receptor complex for interleukin (IL) 1, a key inflammatory cytokine. IL1 receptor complex interacts with MyD88 via the Toll/IL1 receptor (TIR) domain. Here we report structure-function studies that help define the MyD88 TIR domain binding sites involved in IL1-induced protein-protein interactions. The MyD88 TIR domain, employed as a dominant negative inhibitor of IL1 signaling to screen MyD88 TIR mutants, lost its suppressing activity upon truncation of its Box 3. Accordingly, mutations of Box 3 residues 285–286 reversed the dominant negative effect of the MyD88 TIR domain on IL1-induced and NFB-dependent reporter gene activity and IL6 production. Moreover, mutations of residues 171 in helix A, 195–197 in Box 2, and 275 in E-strand had similar functional effects. Strikingly, only mutations of residues 195–197 eliminated the TIR-TIR interaction of MyD88 and IL1 receptor accessory protein (IL1RAcP), whereas substitution of neighboring canonical Pro²⁰⁰ by His was without effect. Mutations in Box 2 and 3 prevented homotypic MyD88 oligomerization via TIR domain. Based on this structure-function analysis, a three-dimensional docking model of TIR-TIR interaction between MyD88 and IL1RAcP was developed.

Received for publication, March 24, 2005

^* This work was supported in part by United States Public Health Service National Institutes of Health Grants HL69542, HL62356, and HL68744. The use of core facilities in this study was supported by National Institutes of Health Grants 2P30CA68485 to the Vanderbilt Ingram Cancer Center and 5P30DK058404-03 to the Vanderbilt Digestive Disease Research Center. 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.

Submitted as partial fulfillment of the requirements for the degree of Doctor of Philosophy, Vanderbilt University School of Medicine.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Vanderbilt University School of Medicine, 1161 21^st Ave. South, A-5321 MCN, Nashville, TN 37232-2363. Tel.: 615-343-8280; Fax: 615-343-8278; E-mail: jacek.hawiger{at}vanderbilt.edu.

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

This article has been cited by other articles:

				H. von Bernuth, C. Picard, Z. Jin, R. Pankla, H. Xiao, C.-L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, et al. Pyogenic Bacterial Infections in Humans with MyD88 Deficiency Science, August 1, 2008; 321(5889): 691 - 696. [Abstract] [Full Text] [PDF]

				M. Loiarro, F. Capolunghi, N. Fanto, G. Gallo, S. Campo, B. Arseni, R. Carsetti, P. Carminati, R. De Santis, V. Ruggiero, et al. Pivotal Advance: Inhibition of MyD88 dimerization and recruitment of IRAK1 and IRAK4 by a novel peptidomimetic compound J. Leukoc. Biol., October 1, 2007; 82(4): 801 - 810. [Abstract] [Full Text] [PDF]

				V. Y. Toshchakov, M. J. Fenton, and S. N. Vogel Cutting Edge: Differential Inhibition of TLR Signaling Pathways by Cell-Permeable Peptides Representing BB Loops of TLRs J. Immunol., March 1, 2007; 178(5): 2655 - 2660. [Abstract] [Full Text] [PDF]

				Z. Jiang, P. Georgel, C. Li, J. Choe, K. Crozat, S. Rutschmann, X. Du, T. Bigby, S. Mudd, S. Sovath, et al. Details of Toll-like receptor:adapter interaction revealed by germ-line mutagenesis PNAS, July 18, 2006; 103(29): 10961 - 10966. [Abstract] [Full Text] [PDF]

				C. N. Davis, E. Mann, M. M. Behrens, S. Gaidarova, M. Rebek, J. Rebek Jr., and T. Bartfai MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics PNAS, February 21, 2006; 103(8): 2953 - 2958. [Abstract] [Full Text] [PDF]