Protein-Protein Interactions in TRAF3

  • Kathryn R. Ely
  • Ramadurgam Kodandapani
  • ShuangDing Wu
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 597)

Abstract

TNF-receptor-associated factors (TRAFs) are intracellular proteins that bind to the cytoplasmic portion of TNF receptors and mediate downstream signaling. The six known TRAF proteins play overlapping yet distinct roles in controlling immune responses as well as cellular processes such as activation of NF-κB and JNK signaling pathways. For example, CD40 binds to TRAF2, TRAF3 and TRAF6 to control B cell differentiation, proliferation and growth.1 In contrast, binding of lymphotoxin-β receptor (LTβR) to TRAF2 and TRAF5 propagates signals leading to activation of NF-κB,2 while binding to TRAF3 induces negative regulation of this pathway and leads to apoptosis in tumor cells.3,4 Binding recognition is mediated by specific contacts of a consensus recognition sequence in the partner with residues in a hydrophobic crevice on the TRAF molecule. Since each of these protein-protein interactions occurs within this same binding crevice, it appears that TRAF-mediated cellular mechanisms may be regulated, in part, by the level of expression or recruitment of the adaptor proteins or receptors that are competing for the crevice.

The specific contacts of CD40, LTβR and BAFF-R have been defined in crystal structures of the complex with TRAF3.5, 6, 7 In addition, the downstream regulator TANK and the viral oncogenic protein LMP1 from the Epstein Barr virus also bind to the same TRAF crevice and these contacts have also been described crystallographically.8,9 Comparison of these five crystal structures has revealed that the recognition motifs in each of these proteins are accommodated in one TRAF3 binding crevice and that the binding interface is structurally and functionally adaptive.10 In this chapter, the molecular details of the interactions will be described and correlated with the functional implications for multiple TRAF3 roles in cellular regulation.

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Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Kathryn R. Ely
    • 1
  • Ramadurgam Kodandapani
  • ShuangDing Wu
  1. 1.The Burnham InstituteLa JollaUSA

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