Crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes: affinity, specificity, and regulation.
TRAF1/2 and cIAP1/2 are members of the TNF receptor-associated factor (TRAF) and the inhibitor of apoptosis (IAP) families, respectively. They are critical for canonical and noncanonical NF-kappaB signaling pathways. Here, we report the crystal structures of the TRAF2: cIAP2 and the TRAF1: TRAF2: cIAP2 complexes. A TRAF2 trimer interacts with one cIAP2 both in the crystal and in solution. Two chains of the TRAF2 trimer directly contact cIAP2, and key residues at the interface are confirmed by mutagenesis. TRAF1 and TRAF2 preferentially form the TRAF1: (TRAF2)(2) heterotrimer, which interacts with cIAP2 more strongly than TRAF2 alone. In contrast, TRAF1 alone interacts very weakly with cIAP2. Surprisingly, TRAF1 and one chain of TRAF2 in the TRAF1: (TRAF2)(2): cIAP2 ternary complex mediate interaction with cIAP2. Because TRAF1 is upregulated by many stimuli, it may modulate the interaction of TRAF2 with cIAP1/2, which explains regulatory roles of TRAF1 in TNF signaling.
Zheng
Chao
C
Weill Medical College, Cornell University, New York, NY 10021, USA.
Kabaleeswaran
Venkataraman
V
Wang
Yaya
Y
Cheng
Genhong
G
Wu
Hao
H
D000595:Amino Acid Sequence; D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D016296:Mutagenesis; D016328:NF-kappa B / Q000378:metabolism; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology; D047990:TNF Receptor-Associated Factor 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D047992:TNF Receptor-Associated Factor 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D051034:Inhibitor of Apoptosis Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D047990:TNF Receptor-Associated Factor 1; D047992:TNF Receptor-Associated Factor 2; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases
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