Mh1 domain of Smad is a degraded homing endonuclease.
Smad proteins are eukarytic transcription regulators in the TGF-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 MH1 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.
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9050, USA. grishin@chop.swmed.edu
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D000595:Amino Acid Sequence; D020134:Catalytic Domain; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D051785:Smad Proteins; D051900:Smad3 Protein; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D004268:DNA-Binding Proteins; C497790:SMAD3 protein, human; D051785:Smad Proteins; D051900:Smad3 Protein; D015534:Trans-Activators; D004706:Endodeoxyribonucleases; C064579:I-Ppo endonuclease; D015032:Zinc