Deconvolving the recognition of DNA shape from sequence

Namiko Abe, Iris Dror, Lin Yang, Matthew Slattery, Tianyin Zhou, Harmen J. Bussemaker, Remo Rohs, Richard S. Mann

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)307-318
Number of pages12
JournalCell
Volume161
Issue number2
DOIs
StatePublished - Apr 9 2015

Bibliographical note

Funding Information:
We thank Barry Honig, David Stern, and members of the R.R., H.J.B., and R.S.M. laboratories for feedback and comments on this project, and Vince FitzPatrick, Gabriella Martini, Todd Riley, and Roumen Voutev for technical assistance. This work was supported by the NIH (grants R01GM058575 to R.S.M., F32GM099160 to N.A., R01GM106056 and U01GM103804 to R.R., and R01HG003008 to H.J.B. and R.R.), the USC-Technion Visiting Fellows Program, and an Alfred P. Sloan Research Fellowship (to R.R.).

Publisher Copyright:
© 2015 Elsevier Inc.

Fingerprint

Dive into the research topics of 'Deconvolving the recognition of DNA shape from sequence'. Together they form a unique fingerprint.

Cite this