Structural basis for DNA recognition by FOXC2

Xiaojuan Chen; Hudie Wei; Jun Li; Xujun Liang; Shuyan Dai; Longying Jiang; Ming Guo; Lingzhi Qu; Zhuchu Chen; Lin Chen; Yongheng Chen

doi:10.1093/nar/gkz077

Structural basis for DNA recognition by FOXC2

Nucleic Acids Res. 2019 Apr 23;47(7):3752-3764. doi: 10.1093/nar/gkz077.

Authors

Xiaojuan Chen^{1

2}, Hudie Wei¹, Jun Li¹, Xujun Liang¹, Shuyan Dai¹, Longying Jiang¹, Ming Guo¹, Lingzhi Qu¹, Zhuchu Chen¹, Lin Chen³, Yongheng Chen^{1

2}

Affiliations

¹ NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
² Key Laboratory of Medical Genetics and College of Life Science, Central South University, Changsha, Hunan 410008, China.
³ Molecular and Computational Biology Program, Department of Biological Sciences and Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

The FOXC family of transcription factors (FOXC1 and FOXC2) plays essential roles in the regulation of embryonic, ocular, and cardiac development. Mutations and abnormal expression of FOXC proteins are implicated in genetic diseases as well as cancer. In this study, we determined two crystal structures of the DNA-binding domain (DBD) of human FOXC2 protein, in complex with different DNA sites. The FOXC2-DBD adopts the winged-helix fold with helix H3 contributing to all the base specific contacts, while the N-terminus, wing 1, and the C-terminus of FOXC2-DBD all make additional contacts with the phosphate groups of DNA. Our structural, biochemical, and bioinformatics analyses allow us to revise the previously proposed DNA recognition mechanism and provide a model of DNA binding for the FOXC proteins. In addition, our structural analysis and accompanying biochemical assays provide a molecular basis for understanding disease-causing mutations in FOXC1 and FOXC2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA / chemistry*
DNA / genetics
DNA-Binding Proteins / chemistry*
DNA-Binding Proteins / genetics
Forkhead Transcription Factors / chemistry*
Forkhead Transcription Factors / genetics
Gene Expression Regulation / genetics
Humans
Mutation
Nucleic Acid Conformation
Protein Domains / genetics

Substances

DNA-Binding Proteins
FOXC1 protein, human
Forkhead Transcription Factors
mesenchyme fork head 1 protein
DNA