TRAF1 binds TRAF2 within TNFR1 signaling complex

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Reaction [binding]
Homo sapiens
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TNF-induced NFkappaB activates a group of gene products including TNF receptor associated factor (TRAF) family members and inhibitor of apoptosis proteins (BIRC or cIAP1/2). TRAFs and cIAP1/2 proteins may function cooperatively at the earliest checkpoint to suppress TNF-α-induced apoptosis (Rothe M et al. 1994,1995; Wang CU et al. 1998).

The TRAFs (TRAF1 to TRAF6) are a group of structurally similar adaptor proteins, in most cases with E3 ligase activity, that are involved in downstream signaling of various cell surface receptors such as TNFR1, TNFR2, CD40, TLRs and TCR (Jang HD et al. 2001; Fotin-Mleczek M et al. 2004; Su X et al. 2006). The hallmark feature of all TRAFs is a C-terminal TRAF-domain of approximately 230 amino acids, which is responsible for homo- and heterooligomerization of TRAF molecules (Rothe M et al. 1994). The differences in amino acid sequences in TRAF-domains define the range of TRAF interaction partners. Another important structural element of TRAFs, with an exception of TRAF1, is the N-terminal RING finger domain that modulates induction of NFkappaB and MAPK activities. As TRAF1 has no RING finger domain, the effects of TRAF1 on NFkB activation are rather unclear. It is believed that TRAF1 regulates TNF receptor activity through its ability to interact with TRAF2 (Rothe M et al.1995; Zheng C et al. 2010; Fotin-Mleczek M et al. 2004). Structural and biochemical studies showed that TRAF1:TRAF2 heterotrimer (1:2) binds BIRC (cIAP2) more strongly than TRAF2 homotrimers, suggesting that TRAF1 may modulate the interaction between TRAF2 and BIRC (cIAP1/2) and thus suppress TNF-alpha induced apoptosis (Zheng C et al. 2010). Noteworthy, TRAF1:TRAF2 heterotrimers and TRAF2 homotrimers also differ in their capability with certain receptors but there seems to be no difference with respect to TNFR1 recruitment (Fotin-Mleczek M et al. 2004). On the contrary, TNF-induced caspase-mediated cleavage of TRAF1 generates a C-terminal fragment with NFkB-inhibitory, pro-apoptotic activity (Leo e et al. 2001; Jang HD et al. 2001; Henkler F et al. 2003). Thus, the current data suggest that depending on its cleavage status TRAF1 may exert either cytoprotective or cytotoxic effect in death domain-containing receptor signaling pathways.

The heteromeric complex TRAF1:TRAF2 has been also implicated in the cross-talk of TNFR1 and TNFR2 (Wicovsky A et al. 2009).

Literature References
PubMed ID Title Journal Year
11181075 Caspase-cleaved TRAF1 negatively regulates the antiapoptotic signals of TRAF2 during TNF-induced cell death

Chung, YM, Lee, SY, Choi, YG, Baik, JH, Jung, YK, Jang, HD, Park, IS

Biochem. Biophys. Res. Commun. 2001
20385093 Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation

Wang, Y, Wu, H, Zheng, C, Cheng, G, Kabaleeswaran, V

Mol. Cell 2010
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