Molecular modeling of mutations in the DNA-binding domain of the oncoprotein Qin.
The retroviral oncogene qin, homologue of mammalian brain factor 1 (FOXG1 B), belongs to the family of winged helix transcription factors. Oncogenic transformation by Qin requires sequence-specific DNA binding. Missense mutations in the forkhead domain of Qin modulate its oncogenic transforming ability in chicken embryonic fibroblasts. We used homology model building (threading) techniques to generate atomic structures of wild-type c-Qin and c-Qin mutants, using the solution structure of the forkhead domain of the adipocyte transcription factor as a template (M. J. van Dongen et al., J. Mol. Biol., 296: 351-359, 2000). Energy calculations indicate that the Qin forkhead structure is stabilized primarily by hydrophobic interactions between residues at the helical interface. None of the missense mutations analyzed here were responsible for maintaining the most critical pairwise interactions holding the forkhead domain together. The mutated proteins form the overall structure of the forkhead domain, but the mutations do interfere with DNA binding.
Banerjee-Basu
Sharmila
S
Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-4470, USA.
Baxevanis
Andreas D
AD
D000595:Amino Acid Sequence; D030161:Avian Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry; D051858:Forkhead Transcription Factors; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000737:chemistry; D015513:Oncogene Proteins; D010802:Phylogeny; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry; D014764:Viral Proteins
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014764:Viral Proteins; C490425:v-qin protein, Avian sarcoma virus 31