Using a structural and logics systems approach to infer bHLH–DNA binding specificity determinants
Name
De Masi-2011-Using a structural and logics systems approach.pdf
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Author(s)
Masi, Federico De
Grove, Christian A.
Vedenko, Anastasia
Alibes, Andreu
Gisselbrecht, Stephen S.
Serrano, Luis
Walhout, Albertha J. M.
Bulyk, Martha L.
Date Issued
February 2011
Journal
Nucleic Acids Research
Publisher
Oxford University Press (OUP)
Citation
De Masi, F. et al. “Using a Structural and Logics Systems Approach to Infer bHLH-DNA Binding Specificity Determinants.” Nucleic Acids Research 39.11 (2011): 4553–4563. Web. 1 June 2012.
Version
Final published version
Abstract
Numerous efforts are underway to determine gene regulatory networks that describe physical relationships between transcription factors (TFs) and their target DNA sequences. Members of paralogous TF families typically recognize similar DNA sequences. Knowledge of the molecular determinants of protein–DNA recognition by paralogous TFs is of central importance for understanding how small differences in DNA specificities can dictate target gene selection. Previously, we determined the in vitro DNA binding specificities of 19 Caenorhabditis elegans basic helix-loop-helix (bHLH) dimers using protein binding microarrays. These TFs bind E-box (CANNTG) and E-box-like sequences. Here, we combine these data with logics, bHLH–DNA co-crystal structures and computational modeling to infer which bHLH monomer can interact with which CAN E-box half-site and we identify a critical residue in the protein that dictates this specificity. Validation experiments using mutant bHLH proteins provide support for our inferences. Our study provides insights into the mechanisms of DNA recognition by bHLH dimers as well as a blueprint for system-level studies of the DNA binding determinants of other TF families in different model organisms and humans.
MIT Department
Harvard University--MIT Division of Health Sciences and Technology
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Creative Commons Attribution Non-Commercial
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DOI of Published Version
https://doi.org/10.1093/nar/gkr070
