DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility

Ricardo Coñuecar; Isabel Asela; Maira Rivera; Pablo Galaz-Davison; Jorge González-Higueras; George L Hamilton; Felipe Engelberger; César A Ramírez-Sarmiento; Jorge Babul; Hugo Sanabria; Exequiel Medina

doi:10.1016/j.isci.2023.107228

DNA facilitates heterodimerization between human transcription factors FoxP1 and FoxP2 by increasing their conformational flexibility

iScience. 2023 Jun 28;26(7):107228. doi: 10.1016/j.isci.2023.107228. eCollection 2023 Jul 21.

Authors

Ricardo Coñuecar¹, Isabel Asela¹, Maira Rivera^{2

3}, Pablo Galaz-Davison^{2

3}, Jorge González-Higueras^{2

3}, George L Hamilton⁴, Felipe Engelberger⁵, César A Ramírez-Sarmiento^{2

3}, Jorge Babul¹, Hugo Sanabria⁶, Exequiel Medina^{1

6}

Affiliations

¹ Departamento de Biología, Facultad de Ciencias, Universidad de Chile, Santiago 7800003, Chile.
² Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile.
³ ANID - Millennium Science Initiative Program - Millennium Institute for Integrative Biology (iBio), Santiago 8331150, Chile.
⁴ Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA.
⁵ Institute for Drug Discovery, Leipzig University Medical School, 04107 Leipzig, Germany.
⁶ Department of Physics & Astronomy, Clemson University, Clemson, SC 29634, USA.

Abstract

Transcription factors regulate gene expression by binding to DNA. They have disordered regions and specific DNA-binding domains. Binding to DNA causes structural changes, including folding and interactions with other molecules. The FoxP subfamily of transcription factors in humans is unique because they can form heterotypic interactions without DNA. However, it is unclear how they form heterodimers and how DNA binding affects their function. We used computational and experimental methods to study the structural changes in FoxP1's DNA-binding domain when it forms a heterodimer with FoxP2. We found that FoxP1 has complex and diverse conformational dynamics, transitioning between compact and extended states. Surprisingly, DNA binding increases the flexibility of FoxP1, contrary to the typical folding-upon-binding mechanism. In addition, we observed a 3-fold increase in the rate of heterodimerization after FoxP1 binds to DNA. These findings emphasize the importance of structural flexibility in promoting heterodimerization to form transcriptional complexes.

Keywords: Biochemistry; Molecular biology; Structural biology.