SKI encodes the nuclear protooncogene protein homolog of avian sarcoma viral (v-ski) oncogene. It functions as a repressor of TGF-beta signaling, and may play a role in neural tube development and muscle differentiation. The structure revealed specific recognition of the SMAD4 L3 loop region by a highly conserved interaction loop (I loop) from SKI.Indeed, SKI disrupted the formation of a functional complex between the comediator SMADs (Co-SMADs) and R-SMADs, explaining how it could lead to repression of TGF-beta, activin, and bone morphogenetic protein responses. The structure of the SKI fragment, stabilized by a bound zinc atom, resembled the SAND domain found in transcription factors and other nuclear proteins, in which the corresponding I loop is responsible for DNA binding.