LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3

ShuangDing Wu; Ping Xie; Kate Welsh; Chenglong Li; Chao-Zhou Ni; Xiuwen Zhu; John C Reed; Arnold C Satterthwait; Gail A Bishop; Kathryn R Ely

doi:10.1074/jbc.M502511200

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LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3

Journal article

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LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3

ShuangDing Wu, Ping Xie, Kate Welsh, Chenglong Li, Chao-Zhou Ni, Xiuwen Zhu, John C Reed, Arnold C Satterthwait, Gail A Bishop and Kathryn R Ely

The Journal of biological chemistry, Vol.280(39), pp.33620-33626

09/30/2005

DOI: 10.1074/jbc.M502511200

PMID: 16009714

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Abstract

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.

Transfection

Viral Matrix Proteins - genetics

Humans

Crystallography, X-Ray

CD40 Antigens - metabolism

B-Lymphocytes - virology

Viral Matrix Proteins - metabolism

Binding Sites

B-Lymphocytes - metabolism

Amino Acid Sequence

Herpesvirus 4, Human - chemistry

Lymphocyte Activation

Models, Molecular

Alanine - metabolism

TNF Receptor-Associated Factor 3 - metabolism

Blotting, Western

Precipitin Tests

Amino Acid Motifs

CD40 Antigens - chemistry

Animals

Viral Matrix Proteins - chemistry

Mice

Cell Transformation, Viral

Microscopy, Fluorescence

Amino Acid Substitution

Details

Title: Subtitle: LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3
Creators: ShuangDing Wu - Cancer Center, The Burnham Institute, La Jolla, California 92037, USA
Ping Xie
Kate Welsh
Chenglong Li
Chao-Zhou Ni
Xiuwen Zhu
John C Reed
Arnold C Satterthwait
Gail A Bishop
Kathryn R Ely
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(39), pp.33620-33626
DOI: 10.1074/jbc.M502511200
PMID: 16009714
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: United States
Grant note: AI49993 / NIAID NIH HHS AI28847 / NIAID NIH HHS CA69381 / NCI NIH HHS CA99997 / NCI NIH HHS
Language: English
Date published: 09/30/2005
Academic Unit: Microbiology and Immunology; President
Record Identifier: 9984001231102771

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