MH1 domain of Smad is a degraded Homing endonuclease

Smad proteins are eukarytic transcription regulators in the TCF-beta signaling cascade. Using a combination of sequence and structure-based analyses, we argue that MH1 domain of Smad is homologous to the diverse His-Me finger endonuclease family enzymes. The similarity is particularly extensive with the I-PpoI endonuclease. In addition to the global fold similarities, both proteins possess a conserved motif of three cysteine residues and one histidine residue which form a zinc-binding site in I-PpoI. Sequence and structure conservation in the motif region strongly suggest that Mi-Il domain may also incorporate a metal ion in its structural core. MH1 of Smad3 and I-PpoI exhibit similar nucleic,acid binding mode and interact with DNA major groove through an antiparallel beta -sheet. MH1 is an example of transcription regulator derived from the ancient enzymatic domain that lost its catalytic activity but retained DNA-binding sites. (C) 2001 Academic Press.