PDBsum entry: 1zms

Signaling protein

PDB id: 1zms

Contents

Protein chain

192 a.a. *

Ligands

PRO-GLN-GLN-ALA-THR-ASP-ASP

* Residue conservation analysis

PDB id:

1zms

Name:

Signaling protein

Title:

Lmp1 protein binds to traf3 as a structural cd40

Structure:

Tnf receptor associated factor 3. Chain: a. Fragment: sequence database residues 377-568. Synonym: cd40 receptor associated factor 1, craf1, cd40 binding protein, cd40bp, lmp1 associated protein, lap1, cap-1. Engineered: yes. Latent membrane protein 1. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: traf3, cap1, craf1. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Synthetic: yes. Other_details: this sequence occurs naturally in the latent membrane protein i of epstein barr virus

Biol. unit:

Hexamer (from PQS)

Resolution:

2.80Å R-factor: 0.206 R-free: 0.255

Authors:

S.D.Wu,P.Xie,K.Welsh,C.Li,C.-Z.Ni,X.Zhu,J.C.Reed, A.C.Satterthwait,G.A.Bishop,K.R.Ely

Key ref:

S.Wu et al. (2005). LMP1 protein from the Epstein-Barr virus is a structural CD40 decoy in B lymphocytes for binding to TRAF3. J Biol Chem, 280, 33620-33626. PubMed id: 16009714 DOI: 10.1074/jbc.M502511200

Date:

10-May-05 Release date: 19-Jul-05

Protein chain

Q13114  (TRAF3_HUMAN) -  TNF receptor-associated factor 3

Seq: 568 a.a.

Struc: 192 a.a.

DOI no: 10.1074/jbc.M502511200

J Biol Chem 280:33620-33626 (2005)

PubMed id: 16009714

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

S.Wu, P.Xie, K.Welsh, C.Li, C.Z.Ni, X.Zhu, J.C.Reed, A.C.Satterthwait, G.A.Bishop, K.R.Ely.

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.

Selected figure(s)

Figure 1.
FIGURE 1. Structure of the LMP1-TRAF3 complex. The complex is shown schematically, with the TRAF3 trimer represented in a ribbon diagram and each subunit colored separately. LMP1 is shown as a gray ball-and-stick model. One molecule of LMP1 binds to each TRAF3 subunit in a crevice at the edge of the TRAF3 -sandwich domain. The TRAF3 trimer is stabilized by coiled-coil interactions between long helices that are at the N terminus of each TRAF3 monomer. In A, the location of the cell membrane would be at the top of the image. In B, the view from the top of the trimer is shown. The 3-fold symmetry is apparent, illustrating that the TRAF3 subunits and the LMP1 molecule are identical and related by strict crystallographic symmetry. In C, the model of LMP1 is displayed in a 2F[o] - F[c] density map contoured at 2.8-Å resolution. Clear strong electron density was visible to define the polypeptide backbone and the orientation of the side chains for the residues labeled: PQQATDD. In D, the contacts for LMP1-TRAF3 recognition are shown. This is a close-up view of the intermolecular contacts in the LMP1-TRAF3 complex, with TRAF3 shown as an orange ribbon and contact residues shown as gray ball-and-stick models. LMP1 is shown as a green ball-and-stick model. Critical contact residues are labeled, and the labels are underlined for residues from TRAF3. Intermolecular and intramolecular hydrogen bonds are drawn as red and green dotted lines, respectively.

Figure 3.
FIGURE 3. LMP1 and CD40 bind to the same binding crevice on TRAF3. The recognition motifs of LMP1 (PQQAT; left panel) and CD40 (PVQET; right panel) are shown in their bound configurations in the shallow binding crevice on the surface of TRAF3. The binding crevice is shown as a molecular surface colored according to electrostatic characteristics, with blue corresponding to negative regions, red representing positive regions, and white corresponding to neutral regions. The view of the two complexes is in the same orientation for direct comparison. The surface residues of TRAF3 undergo conformational adjustments as a mechanism for molecular adaptation (32), and the effect of the adaptations can be seen in the differences in electrostatic patterns when the two receptors are bound. Overall, the conformation of the recognition motif in LMP1 mimics that in CD40.

The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 33620-33626) copyright 2005.

Figures were selected by the author.