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FOXO transcription factors differ in their dynamics and intra/intermolecular interactions.

ABSTRACT: Transcription factors play key roles in orchestrating a plethora of cellular mechanisms and controlling cellular homeostasis. Transcription factors share distinct DNA binding domains, which allows to group them into protein families. Among them, the Forkhead box O (FOXO) family contains transcription factors crucial for cellular homeostasis, longevity and response to stress. The dysregulation of FOXO signaling is linked to drug resistance in cancer therapy or cellular senescence, however, selective drugs targeting FOXOs are limited, thus knowledge about structure and dynamics of FOXO proteins is essential. Here, we provide an extensive study of structure and dynamics of all FOXO family members. We identify residues accounting for different dynamic and structural features. Furthermore, we show that the auto-inhibition of FOXO proteins by their C-terminal trans-activation domain is conserved throughout the family and that these interactions are not only possible intra-, but also inter-molecularly. This indicates a model in which FOXO transcription factors would modulate their activities by interacting mutually.

SUBMITTER: Spreitzer E

PROVIDER: S-EPMC9097636 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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FOXO transcription factors differ in their dynamics and intra/intermolecular interactions.

Spreitzer Emil E Alderson T Reid TR Bourgeois Benjamin B Eggenreich Loretta L Habacher Hermann H Brahmersdorfer Greta G Pritišanac Iva I Sánchez-Murcia Pedro A PA Madl Tobias T

Current research in structural biology 20220427

Transcription factors play key roles in orchestrating a plethora of cellular mechanisms and controlling cellular homeostasis. Transcription factors share distinct DNA binding domains, which allows to group them into protein families. Among them, the Forkhead box O (FOXO) family contains transcription factors crucial for cellular homeostasis, longevity and response to stress. The dysregulation of FOXO signaling is linked to drug resistance in cancer therapy or cellular senescence, however, select ...[more]

PMID: 35573459

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Project description:The O-H...N and O-H...O hydrogen bonds were investigated in 10-hydroxybenzo[h]quinoline (HBQ) and benzo[h]quinoline-2-methylresorcinol complex in vacuo, solvent and crystalline phases. The chosen systems contain analogous donor and acceptor moieties but differently coupled (intra- versus intermolecularly). Car-Parrinello molecular dynamics (CPMD) was employed to shed light onto principle components of interactions responsible for the self-assembly. It was applied to study the dynamics of the hydrogen bonds and vibrational features as well as to provide initial geometries for incorporation of quantum effects and electronic structure studies. The vibrational features were revealed using Fourier transformation of the autocorrelation function of atomic velocity and by inclusion of nuclear quantum effects on the O-H stretching solving vibrational Schrödinger equation a posteriori. The potential of mean force (Pmf) was computed for the whole trajectory to derive the probability density distribution and for the O-H stretching mode from the proton vibrational eigenfunctions and eigenvalues incorporating statistical sampling and nuclear quantum effects. The electronic structure changes of the benzo[h]quinoline-2-methylresorcinol dimer and trimers were studied based on Constrained Density Functional Theory (CDFT) whereas the Electron Localization Function (ELF) method was applied for all systems. It was found that the bridged proton is localized on the donor side in both investigated systems in vacuo. The crystalline phase simulations indicated bridged proton-sharing and transfer events in HBQ. These effects are even more pronounced when nuclear quantization is taken into account, and the quantized Pmf allows the proton to sample the acceptor area more efficiently. The CDFT indicated the charge depletion at the bridged proton for the analyzed dimer and trimers in solvent. The ELF analysis showed the presence of the isolated proton (a signature of the strongest hydrogen bonds) only in some parts of the HBQ crystal simulation. The collected data underline the importance of the intramolecular coupling between the donor and acceptor moieties.

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FOXO transcription factors differ in their dynamics and intra/intermolecular interactions.

Publications

FOXO transcription factors differ in their dynamics and intra/intermolecular interactions.

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