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Cell. 2015 Apr 9;161(2):307-18. doi: 10.1016/j.cell.2015.02.008. Epub 2015 Apr 2.

Deconvolving the recognition of DNA shape from sequence.

Author information

1
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
2
Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Biology, Technion - Israel Institute of Technology, Haifa 32000, Israel.
3
Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
4
Department of Biomedical Sciences, University of Minnesota Medical School, Duluth, MN 55812, USA.
5
Department of Biological Sciences, Columbia University, New York, NY 10032, USA.
6
Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA; Department of Physics and Astronomy, University of Southern California, Los Angeles, CA 90089, USA; Department of Computer Science, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: rohs@usc.edu.
7
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA. Electronic address: rsm10@columbia.edu.

Abstract

Protein-DNA binding is mediated by the recognition of the chemical signatures of the DNA bases and the 3D shape of the DNA molecule. Because DNA shape is a consequence of sequence, it is difficult to dissociate these modes of recognition. Here, we tease them apart in the context of Hox-DNA binding by mutating residues that, in a co-crystal structure, only recognize DNA shape. Complexes made with these mutants lose the preference to bind sequences with specific DNA shape features. Introducing shape-recognizing residues from one Hox protein to another swapped binding specificities in vitro and gene regulation in vivo. Statistical machine learning revealed that the accuracy of binding specificity predictions improves by adding shape features to a model that only depends on sequence, and feature selection identified shape features important for recognition. Thus, shape readout is a direct and independent component of binding site selection by Hox proteins.

PMID:
25843630
PMCID:
PMC4422406
DOI:
10.1016/j.cell.2015.02.008
[Indexed for MEDLINE]
Free PMC Article

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