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

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

Biochemistry and Cell Biology

Brigham and Women’s Hospital
Harvard University
Dana-Farber Cancer Institute

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

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.

Original language	English
Pages (from-to)	245-253.e6
Journal	Molecular Cell
Volume	74
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2019.01.019
State	Published - Apr 18 2019

Keywords

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

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10.1016/j.molcel.2019.01.019

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@article{0e87ffdccdb149bd9f412c9d369e114c,

title = "Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes",

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 = "co-crystal structures, DNA binding sites, DNA shape, forkhead, gene regulation, protein-DNA interactions, specificity, transcription factors",

author = "Rogers, \{Julia M.\} and Waters, \{Colin T.\} and Seegar, \{Tom C.M.\} and Jarrett, \{Sanchez M.\} and Hallworth, \{Amelia N.\} and Blacklow, \{Stephen C.\} and Bulyk, \{Martha L.\}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = apr,

day = "18",

doi = "10.1016/j.molcel.2019.01.019",

language = "English",

volume = "74",

pages = "245--253.e6",

journal = "Molecular Cell",

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TY - JOUR

T1 - Bispecific Forkhead Transcription Factor FoxN3 Recognizes Two Distinct Motifs with Different DNA Shapes

AU - Rogers, Julia M.

AU - Waters, Colin T.

AU - Seegar, Tom C.M.

AU - Jarrett, Sanchez M.

AU - Hallworth, Amelia N.

AU - Blacklow, Stephen C.

AU - Bulyk, Martha L.

PY - 2019/4/18

Y1 - 2019/4/18

N2 - 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.

AB - 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.

KW - co-crystal structures

KW - DNA binding sites

KW - DNA shape

KW - forkhead

KW - gene regulation

KW - protein-DNA interactions

KW - specificity

KW - transcription factors

UR - https://www.scopus.com/pages/publications/85064256419

U2 - 10.1016/j.molcel.2019.01.019

DO - 10.1016/j.molcel.2019.01.019

M3 - Article

C2 - 30826165

AN - SCOPUS:85064256419

SN - 1097-2765

VL - 74

SP - 245-253.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 2

ER -

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

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Keywords

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