Intrinsically Disordered Regions of the DNA-Binding Domain of Human FoxP1 Facilitate Domain Swapping

JOURNAL OF MOLECULAR BIOLOGY

卷:432

Article

Medina, Exequiel¹  Villalobos, Pablo¹  Hamilton, George L.²  Komives, Elizabeth A.³  Sanabria, Hugo²  Ramirez-Sarmiento, Cesar A.^4,5,6,7  Babul, Jorge¹ 

[1] Univ Chile, Fac Ciencias, Dept Biol, Las Palmeras 3425,Casilla 653, Santiago 7800003, Chile

[2] Clemson Univ, Dept Phys & Astron, Clemson, SC 29634 USA

[3] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA USA

[4] Pontificia Univ Catolica Chile, Sch Engn, Inst Biol & Med Engn, Santiago, Chile

[5] Pontificia Univ Catolica Chile, Sch Med, Inst Biol & Med Engn, Santiago, Chile

[6] Pontificia Univ Catolica Chile, Sch Biol Sci, Inst Biol & Med Engn, Santiago, Chile

[7] Millennium Inst Integrat Biol iBio, Santiago, Chile

关键词: transcription factors;    single-molecule Forster resonance energy transfer;    hydrogen-deuterium exchange mass spectrometry;    domain-swapped forkhead domain;    molecular dynamics simulations;   

DOI  :  10.1016/j.jmb.2020.07.017

来源: Elsevier

【 摘 要 】

Forkhead box P (FoxP) proteins are unique transcription factors that spatiotemporally regulate gene expression by tethering two chromosome loci together via functional domain-swapped dimers formed through their DNA-binding domains. Further, the differential kinetics on this dimerization mechanism underlie an intricate gene regulation network at physiological conditions. Nonetheless, poor understanding of the structural dynamics and steps of the association process impedes to link the functional domain swapping to human-associated diseases. Here, we have characterized the DNA-binding domain of human FoxP1 by integrating single-molecule Forster resonance energy transfer and hydrogen-deuterium exchange mass spectrometry data with molecular dynamics simulations. Our results confirm the formation of a previously postulated domain-swapped (DS) FoxP1 dimer in solution and reveal the presence of highly populated, heterogeneous, and locally disordered dimeric intermediates along the dimer dissociation pathway. The unique features of FoxP1 provide a glimpse of how intrinsically disordered regions can facilitate domain swapping oligomerization and other tightly regulated association mechanisms relevant in biological processes. (C) 2020 The Authors. Published by Elsevier Ltd.

【 授权许可】

Free