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

J. Biol. Chem., Vol. 280, Issue 39, 33620-33626, September 30, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/39/33620    most recent M502511200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, S. Articles by Ely, K. R. Search for Related Content PubMed PubMed Citation Articles by Wu, S. Articles by Ely, K. R. Social Bookmarking                      What's this?

LMP1 Protein from the Epstein-Barr Virus Is a Structural CD40 Decoy in B Lymphocytes for Binding to TRAF3^*

ShuangDing Wu, Ping Xie1, Kate Welsh, Chenglong Li2, Chao-Zhou Ni, Xiuwen Zhu2, John C. Reed, Arnold C. Satterthwait, Gail A. Bishop, and Kathryn R. Ely3

From the Cancer Center, The Burnham Institute, La Jolla, California 92037 and the Departments of Microbiology and Internal Medicine, University of Iowa, and the Veterans Affairs Medical Center, Iowa City, Iowa 52242

Epstein-Barr virus is a human herpesvirus that causes infectious mononucleosis and lymphoproliferative malignancies. LMP1 (latent membrane protein-1), which is encoded by this virus and which is essential for transformation of B lymphocytes, acts as a constitutively active mimic of the tumor necrosis factor receptor (TNFR) CD40. LMP1 is an integral membrane protein containing six transmembrane segments and a cytoplasmic domain at the C terminus that binds to intracellular TNFR-associated factors (TRAFs). TRAFs are intracellular co-inducers of downstream signaling from CD40 and other TNFRs, and TRAF3 is required for activation of B lymphocytes by LMP1. Cytoplasmic C-terminal activation region 1 of LMP1 bears a motif (PQQAT) that conforms to the TRAF recognition motif PVQET in CD40. In this study, we report the crystal structure of this portion of LMP1 C-terminal activation region-1 (²⁰⁴PQQATDD²¹⁰) bound in complex with TRAF3. The PQQAT motif is bound in the same binding crevice on TRAF3 where CD40 is bound, providing a molecular mechanism for LMP1 to act as a CD40 decoy for TRAF3. The LMP1 motif is presented in the TRAF3 crevice as a close structural mimic of the PVQET motif in CD40, and the intermolecular contacts are similar. However, the viral protein makes a unique contact: a hydrogen bond network formed between Asp²¹⁰ in LMP1 and Tyr³⁹⁵ and Arg³⁹³ in TRAF3. This intermolecular contact is not made in the CD40-TRAF3 complex. The additional hydrogen bonds may stabilize the complex and strengthen the binding to permit LMP1 to compete with CD40 for binding to the TRAF3 crevice, influencing downstream signaling to B lymphocytes and contributing to dysregulated signaling by LMP1.

Received for publication, March 7, 2005 , and in revised form, June 9, 2005.

The atomic coordinates and structure factors (code 1ZMS) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by National Institutes of Health Grants CA69381, AI28847, AI49993, and CA99997 and a Veterans Affairs career award (to G. A. B.). 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.

¹ Special Fellow of the Leukemia and Lymphoma Society.

² Present address: The Scripps Research Inst., La Jolla, CA 92037.

³ To whom correspondence should be addressed: The Burnham Inst., 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-646-3135; Fax: 858-646-3105; E-mail: ely{at}burnham.org.

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

This article has been cited by other articles:

				P. J. Alff, N. Sen, E. Gorbunova, I. N. Gavrilovskaya, and E. R. Mackow The NY-1 Hantavirus Gn Cytoplasmic Tail Coprecipitates TRAF3 and Inhibits Cellular Interferon Responses by Disrupting TBK1-TRAF3 Complex Formation J. Virol., September 15, 2008; 82(18): 9115 - 9122. [Abstract] [Full Text] [PDF]

				B. A. Mainou, D. N. Everly Jr., and N. Raab-Traub Unique Signaling Properties of CTAR1 in LMP1-Mediated Transformation J. Virol., September 15, 2007; 81(18): 9680 - 9692. [Abstract] [Full Text] [PDF]