Adhesion Molecules-28

Advances and Experimental-4

Aging-9

Agricultural Biotechnology-37

Angiogenesis-29

Antisense-4

Apoptosis-49

Atherosclerosis-12

Autoimmunity-69

Bacterial Virulence-18

Bioinformatics-13

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Biotechnology-102

Cancer Genetics-25

Cancer Metastasis-19

Cell Biology-16

Cell Cycle-34

Cell Metabolism-327

Channels and Transporters-79

Chaperones-11

Circadian Rhythms-13

Coagulation-14

Cytokines/Growth Factors-52

Development-223

DNA-56

DNA Surveillance and Repair-42

Drug Design-17

Endocrine-66

Evolution-33

Extracellular Matrix-30

Gastroenterology-52

Gene Expression-178

Gene Therapy-53

Heart-61

Heat Shock Proteins-19

Hematology-11

Immunology-93

Infectious Disease-71

Ischemia-Reperfusion-33

Leptin and Leptin Antagonists-1

Medical-26

MHC-17

Mitochondria-17

Molecular Biology-45

Molecular Complexes and Signaling-1

Nanomedicine-30

Neurodegenerative Disease-72

Neuropharmacology-112

Neuroscience-38

Nucleus-15

Oncogenes-8

Oncology-87

Parasitic Disease-12

Pharmacogenomics-14

Prebiotic Evolution-6

Protein-12

Reproductive Biology-60

RNA-152

Signal Transduction-186

Stem Cells-80

Surgery-37

T-Cell Activation-12

Tissue Engineering-116

Transplant-51

Vaccines-82

Viruses-85

Chapter category: Signal Transduction

Protein-Protein Interactions in TRAF3

Chapter authors:
Kathryn R. Ely, Ramadurgam Kodandapani and ShuangDing Wu

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-kB 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-b receptor (LTbR) to TRAF2 and TRAF5 propagates signals leading to activation of NF-kB,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, LTbR and BAFF-R have been defined in crystal structures of the complex with TRAF3.5-7 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.

Kathryn R. Ely
The Burnham Institute

Ramadurgam Kodandapani
The Burnham Institute

ShuangDing Wu
The Burnham Institute

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