Structural mechanism of Smad4 recognition by the nuclear oncoprotein Ski: insights on Ski-mediated repression of TGF-beta signaling.

The Ski family of nuclear oncoproteins represses TGF-beta signaling through interactions with the Smad proteins. The crystal structure of the Smad4 binding domain of human c-Ski in complex with the MH2 domain of Smad4 reveals specific recognition of the Smad4 L3 loop region by a highly conserved interaction loop (I ...
loop) from Ski. The Ski binding surface on Smad4 significantly overlaps with that required for binding of the R-Smads. Indeed, Ski disrupts the formation of a functional complex between the Co- and R-Smads, explaining how it could lead to repression of TGF-beta, activin, and BMP responses. Intriguingly, the structure of the Ski fragment, stabilized by a bound zinc atom, resembles the SAND domain, in which the corresponding I loop is responsible for DNA binding.
Mesh Terms:
Amino Acid Sequence, Cell Line, Transformed, DNA-Binding Proteins, Humans, Models, Molecular, Molecular Sequence Data, Mutagenesis, Nuclear Proteins, Protein Structure, Tertiary, Proto-Oncogene Proteins, Signal Transduction, Smad4 Protein, Trans-Activators, Transforming Growth Factor beta, Tumor Cells, Cultured
Date: Nov. 01, 2002
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