The coiled-coil coactivator (CoCoA) is involved in transcriptional activation of target genes by nuclear receptors and the xenobiotic aryl hydrocarbon receptor, as well as target genes of the Wnt signaling pathway, which is mediated by the lymphocyte enhancer factor (LEF)/T cell factor transcription factors and the coactivator -catenin. The recruitment of CoCoA by nuclear receptors is accomplished by the interaction of the central coiled-coiled domain of CoCoA with p160 coactivators; the C-terminal activation domain (AD) of CoCoA is used for downstream signaling, while the function of the N-terminal region was undefined. Here we report that the N-terminus of CoCoA contains another AD, which is necessary and sufficient for synergistic activation of LEF1-mediated transcription by CoCoA and -catenin. The N-terminal AD contains a p300 binding motif, which is important for synergistic cooperation of CoCoA and p300 as coactivators for LEF1 and -catenin. p300 contributes to the function of the CoCoA N-terminal AD primarily through its histone acetyltransferase activity. Moreover, in cultured cells endogenous p300 is recruited to the promoter of an integrated reporter gene by the N-terminus of CoCoA. Thus, the coactivator function of CoCoA for nuclear receptors and LEF1/-catenin involves differential utilization of two different CoCoA ADs.