Relationship between the DNA Binding Domains of SMAD and NFI/CTF Transcription Factors Defines a New Superfamily of Genes

Transcription factors of the SMAD family relay signals from cell surface receptors to the nucleus in response to TGF-beta related soluble factors. Members of the nuclear factor I/CAAT box binding family (NFI/CTF) have been implicated as regulators of diverse biological processes such as adenovirus replication and transcription of TGF-responsive genes. There are highly conserved DNA binding domains in SMAD and NFI/CTF transcription factors that allow sequence specific DNA binding for members of each family. However, no homology relationship has been established for the DNA binding domains present in these families. For a better understanding of the structure and evolution of SMAD genes, we carried out a sensitive PSI-BLAST database search. This revealed significant similarities between the DNA binding domains of SMADs and NFI/CTF transcription factors. Enhanced graphic matrix analysis and multiple sequence alignment of the amino acid sequences of the SMAD and NFI/CTF DNA binding domains also show that these two classes of domains share considerable structural similarity. These results strongly suggest that these two classes of factors share a homologous DNA binding domain presumably resulting from a common ancestry. In contrast, the C-terminal transcription modulation domains of both SMAD and NFI/CTF families do not show any sequence similarity. Based on the structural relationship of their DNA binding domains, we propose that the SMAD and NFI/CTF transcription factors belong to new superfamily of genes.