Molecular Biology

Reengineering Engrailed

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Science  04 Jul 2008:
Vol. 321, Issue 5885, pp. 16
DOI: 10.1126/science.321.5885.16c

The potential for engineering transcription factors so that they bind to specified DNA sequences and work as chemotherapeutic agents or sensors has generated a great deal of excitement. AT-rich sequences have been particularly challenging targets for zinc finger-domain approaches.

Noyes et al. have turned to the other large category of sequence-specific transcription factors, homeodomain proteins. They have carried out a comprehensive survey of the breadth of specificity of the 84 known Drosophila homeodomains that function independently of other DNA-binding domains. The relations between particular amino acid residues and preferred binding sequence were complex, but general determinants were assigned according to whether they cooperated or competed in binding character, leading to predictions for the binding specificity of roughly 75% of the homeodomains in the human genome and allowing them to modify Engrailed to exhibit a binding specificity resembling that of TGIF even though these proteins share only 25% amino acid identity. On the basis of their analysis, the authors have created a Web-based tool that supports the prediction of specificities for homeodomains from other organisms. — BJ

Cell 133, 1277 (2008).

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