Structural Heterogeneity and Dynamics of the Unfolded Ensemble

Echeverria, Ignacia; Papoian, Garegin A.

doi:10.1002/ijch.201400030

Cited by 2 publications

(4 citation statements)

References 99 publications

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“…Nevertheless, evidence supports an unphosphorylated CTD existing as a compact structural ensemble, capable of extending as a function of phosphorylation. Such an ensemble is consistent with emerging structural understanding of intrinsically disordered proteins (IDPs), which can be more compact than chemically denatured proteins of the same size, and can be structurally heterogeneous, possessing transient structural features 17 18 19 20 .…”

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confidence: 76%

Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain

Portz

Gibbs

et al. 2017

Nat Commun

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RNA polymerase II contains a repetitive, intrinsically disordered, C-terminal domain (CTD) composed of heptads of the consensus sequence YSPTSPS. The CTD is heavily phosphorylated and serves as a scaffold, interacting with factors involved in transcription initiation, elongation and termination, RNA processing and chromatin modification. Despite being a nexus of eukaryotic gene regulation, the structure of the CTD and the structural implications of phosphorylation are poorly understood. Here we present a biophysical and biochemical interrogation of the structure of the full length CTD of Drosophila melanogaster, which we conclude is a compact random coil. Surprisingly, we find that the repetitive CTD is structurally heterogeneous. Phosphorylation causes increases in radius, protein accessibility and stiffness, without disrupting local structural heterogeneity. Additionally, we show the human CTD is also structurally heterogeneous and able to substitute for the D. melanogaster CTD in supporting fly development to adulthood. This finding implicates conserved structural organization, not a precise array of heptad motifs, as important to CTD function.

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confidence: 76%

Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain

Portz

Gibbs

et al. 2017

Nat Commun

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“…An alternative approach to quantify the conformational heterogeneity is to determine the distribution of the pairwise RMSD or Q between all sampled structure, as discussed in the Supporting Information (Figure S2). 45,66 Below, we further elaborate on the way the various levels of acetylation structurally affect the conformational preferences of the tails.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…These results again indicate that the monoacetylation of K16 stands out from the overall trend, crucially altering the conformational landscape of the H4 histone tail. An alternative approach to quantify the conformational heterogeneity is to determine the distribution of the pairwise RMSD or Q between all sampled structure, as discussed in the Supporting Information (Figure S2). , Below, we further elaborate on the way the various levels of acetylation structurally affect the conformational preferences of the tails.…”

Section: Resultsmentioning

confidence: 99%

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The Acetylation Landscape of the H4 Histone Tail: Disentangling the Interplay between the Specific and Cumulative Effects

et al. 2015

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Histone tails, the intrinsically disordered terminal regions of histone proteins, are key modulators of the structure and dynamics of chromatin and, consequently, are central to many DNA template-directed processes including replication, repair, and transcription. Acetylation of histone tails is a major post-translational modification (PTM) involved in regulating chromatin, yet it remains unclear how acetylation modifies the disordered state of histone tails and affects their function. We investigated the consequences of increasing acetylation on the isolated H4 histone tail by characterizing the conformational ensembles of unacetylated, mono-, di-, tri-, and tetra-acetylated H4 histone tails using Replica Exchange Molecular Dynamics (REMD) simulations. We found that progressive acetylation has a cumulative effect on the H4 tail, decreasing conformational heterogeneity, increasing helical propensity, and increasing hydrogen bond occupancies. The monoacetylation of lysine 16, however, has unique and specific effects: drastically decreasing the conformational heterogeneity of the H4 tail and leading to highly localized helical secondary structure and elongated conformations. We describe how the cumulative effects of acetylation arise from the charge reduction and increased hydrophobicity associated with adding acetyl groups, while the specific effects are a consequence of steric interactions that are sequence specific. Additionally, we found that increasing the level of acetylation results in the formation of spatially clustered lysines that could serve as recognition patches for binding of chromatin regulating proteins. Hence, we explore the mechanisms by which different acetylation patterns may result in specific recognition of the H4 histone tails by protein or DNA binding partners.

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Structural Heterogeneity and Dynamics of the Unfolded Ensemble

Cited by 2 publications

References 99 publications

Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain

Structural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain

The Acetylation Landscape of the H4 Histone Tail: Disentangling the Interplay between the Specific and Cumulative Effects

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