The intracellular regions of tumor necrosis factors receptors (TNFR) associate with either of two adapter protein types. One is death domain (DD) adapter proteins and another is TNF receptor-associated factors (TRAF).
TNF receptors that directly recruit TRAFs involve a TRAF interaction motif (TIM), a short cytoplasmic sequence with an extended conformation. In humans, TRAF2 is the best characterized one of TRAF. Once TNFR and TRAF2 combine, the Jun N-terminal kinases (JNK) pathway and NF-KB pathway is triggered, leading to diverse functions including cell differentiation, proliferation and inflammatory response. Structural studies about TRAF2 reveal that the molecule forms a stable trimer in solution. Therefore, it is likely that upon engagement with ligands, the trimerized TNF receptors bind a trimeric intracellular TRAF adapter protein with high avidity. After recruitment by the TNF receptors, TRAF2 activates protein kinases that start the JNK pathway or the NF-KB pathway. TRAFs are major signal transducers for the TNF superfamily as well as the IL-1 family proteins.
TNFRs that recruit DD adapter proteins contain a cytoplasmic DD-binding module, composed of 6 a-helices. These receptor DDs form homotypic interactions with the structurally conserved DDs in adapter proteins such as Fas-associated DD protein (FADD) and TNFR-associated DD protein (TRADD). FADD is recruited by receptors, such as Fas, DR4 and DR5. These interactions lead the formation of the death-inducing signaling complex (DISC), and activate the cleavage of caspases 8 and 10, and induce apoptosis. Other TNFRs including TNFR1 and DR3 bind TRADD. TRADD is capable of recruiting FADD through the DD interactions and transmits pro-apoptotic signaling. Alternatively, TRADD can recruit TRAF2 and a serine/threonine kinase receptor-interacting protein (RIP). These two proteins function synergistically to activate the NF-KB pathway, which suppresses apoptotic signaling, promoting cellular proliferation, and initiates inflammatory responses.
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