High Conformational Flexibility of the E2F1/DP1/DNA Complex. Issue 18 (3rd September 2021)

• Record Type: Journal Article
• Authors: Saad, Dana; Paissoni, Cristina; Chaves-Sanjuan, Antonio; Nardini, Marco; Mantovani, Roberto; Gnesutta, Nerina; Camilloni, Carlo
• Is Part Of: Journal of molecular biology. Volume 433:Issue 18(2021)
• Publication Date: 2021-09-03
• Subjects: transcription factor -- E2F -- DP1 -- SAXS -- molecular dynamics; TF Transcription Factor -- DBD DNA-binding Domain -- TAD Trans-Activation Domain -- CC coiled-coil -- MB marked box -- DCM DBD-CC-MB -- SEC size exclusion chromatography -- SAXS Small-Angle X-ray Scattering -- MD Molecular Dynamics -- RMSF Root mean square fluctuations -- IMAC ion-metal affinity chromatography; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167119
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: The structure and dynamics of the E2F1/DP1/DNA complex is modelled. E2F1 and DP1 play a different role in the dynamics of the system. DP1 flexibility may be relevant for protein–protein and protein-DNA interactions. Abstract: The E2F1 transcription factor is a master regulator of cell-cycle progression whose uncontrolled activation contributes to tumor cells growth. E2F1 binds DNA as a heterodimer with DP partners, resulting in a multi-domain quaternary-structure complex composed of DNA binding domains, a coiled coil domain and a marked box domain separated by short linkers. Building on the 3D knowledge of the single domains of E2F and DPs, we characterized the structure and dynamics of the complete E2F1/DP1/DNA complex by a combination of small-angle X-ray scattering and molecular dynamics simulations. It shows an asymmetric contribution of the dynamics of the two proteins. Namely, the coiled-coil domain leans toward the DP1 side of the complex; the DP1 loop between α2 and α3 of the DBD partially populates a helical structure leaning far from the DNA and in the same direction of the coiled-coil domain; and the N-terminal disordered region of DP1, rich in basic residues, contributes to DNA binding stabilization. Intriguingly, tumor mutations in the flexible regions of the complex suggest that perturbation of protein dynamics could affect protein function in a context-dependent way. Our data suggest fundamental contributions of DP proteins in distinct aspects of E2F biology.