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Molecular modeling of mutations in the DNA-binding domain of the oncoprotein Qin

Sharmila Banerjee-Basu1, Andreas D Baxevanis

  • 1Genome Technology Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892-4470, USA.

Molecular Cancer Therapeutics
|December 14, 2002
PubMed

Insights

The oncogene Qin, a FOXG1B homolog, requires DNA binding for oncogenic transformation. Mutations in its forkhead domain disrupt DNA binding, affecting its transforming ability in fibroblasts.

Area of Science:

  • Molecular Biology
  • Oncology
  • Structural Biology

Background:

  • The retroviral oncogene Qin is a homolog of mammalian brain factor 1 (FOXG1B) and a winged helix transcription factor.
  • Oncogenic transformation mediated by Qin is dependent on its ability to bind DNA in a sequence-specific manner.

Purpose of the Study:

  • To investigate the structural basis of Qin's oncogenic activity.
  • To determine how missense mutations in the forkhead domain of Qin affect its structure and DNA-binding capability.
  • To elucidate the role of DNA binding in Qin-induced oncogenic transformation.

Main Methods:

  • Homology modeling (threading) techniques were employed to generate atomic structures of wild-type c-Qin and c-Qin mutants.
  • The solution structure of the forkhead domain of the adipocyte transcription factor was used as a template for modeling.
  • Energy calculations were performed to analyze the stability of the Qin forkhead domain structure.

Main Results:

  • The Qin forkhead domain structure is primarily stabilized by hydrophobic interactions at the helical interface.
  • None of the analyzed missense mutations disrupted the critical pairwise interactions maintaining the forkhead domain's integrity.
  • While mutated proteins retained the overall forkhead domain structure, mutations significantly interfered with DNA binding.

Conclusions:

  • Sequence-specific DNA binding is essential for the oncogenic transformation activity of Qin.
  • Mutations within the forkhead domain of Qin impair its DNA-binding ability, thereby modulating its oncogenic potential.
  • Structural integrity of the forkhead domain is necessary but not sufficient for Qin's oncogenic function; DNA binding is a critical determinant.

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