TY - JOUR
T1 - Deconvolving the recognition of DNA shape from sequence
AU - Abe, Namiko
AU - Dror, Iris
AU - Yang, Lin
AU - Slattery, Matthew
AU - Zhou, Tianyin
AU - Bussemaker, Harmen J.
AU - Rohs, Remo
AU - Mann, Richard S.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/4/9
Y1 - 2015/4/9
N2 - Summary 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.
AB - Summary 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.
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U2 - 10.1016/j.cell.2015.02.008
DO - 10.1016/j.cell.2015.02.008
M3 - Article
C2 - 25843630
AN - SCOPUS:84930409407
SN - 0092-8674
VL - 161
SP - 307
EP - 318
JO - Cell
JF - Cell
IS - 2
ER -