Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes

Julia M Rogers; Colin T Waters; Tom C M Seegar; Sanchez M Jarrett; Amelia N Hallworth; Stephen C Blacklow; Martha L Bulyk

doi:10.1016/j.molcel.2019.01.019

Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes

Mol Cell. 2019 Apr 18;74(2):245-253.e6. doi: 10.1016/j.molcel.2019.01.019. Epub 2019 Feb 27.

Authors

Julia M Rogers¹, Colin T Waters², Tom C M Seegar³, Sanchez M Jarrett⁴, Amelia N Hallworth⁵, Stephen C Blacklow⁶, Martha L Bulyk⁷

Affiliations

¹ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA.
² Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA.
³ Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
⁵ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁶ Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA; Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: stephen_blacklow@hms.harvard.edu.
⁷ Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA; Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: mlbulyk@genetics.med.harvard.edu.

Abstract

Transcription factors (TFs) control gene expression by binding DNA recognition sites in genomic regulatory regions. Although most forkhead TFs recognize a canonical forkhead (FKH) motif, RYAAAYA, some forkheads recognize a completely different (FHL) motif, GACGC. Bispecific forkhead proteins recognize both motifs, but the molecular basis for bispecific DNA recognition is not understood. We present co-crystal structures of the FoxN3 DNA binding domain bound to the FKH and FHL sites, respectively. FoxN3 adopts a similar conformation to recognize both motifs, making contacts with different DNA bases using the same amino acids. However, the DNA structure is different in the two complexes. These structures reveal how a single TF binds two unrelated DNA sequences and the importance of DNA shape in the mechanism of bispecific recognition.

Keywords: DNA binding sites; DNA shape; co-crystal structures; forkhead; gene regulation; protein-DNA interactions; specificity; transcription factors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amino Acid Sequence / genetics
Base Sequence / genetics
Binding Sites / genetics
Cell Cycle Proteins / chemistry*
Cell Cycle Proteins / genetics
Crystallography, X-Ray
DNA / chemistry*
DNA / genetics
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / genetics
Forkhead Transcription Factors
Gene Expression Regulation / genetics
Humans
Multiprotein Complexes / chemistry
Multiprotein Complexes / genetics
Nucleic Acid Conformation*
Nucleotide Motifs / genetics
Regulatory Sequences, Nucleic Acid / genetics
Repressor Proteins / chemistry*
Repressor Proteins / genetics

Substances

Cell Cycle Proteins
DNA-Binding Proteins
FOXN3 protein, human
Forkhead Transcription Factors
Multiprotein Complexes
Repressor Proteins
DNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding