Dynamic Studies on Intrinsically Disordered Regions of Two Paralogous Transcription Factors Reveal Rigid Segments with Important Biological Functions

Maiti, Snigdha; Acharya, Bidisha; Boorla, Veda Sheersh; Manna, Bharat; Ghosh, Amit; De, Soumya

doi:10.1016/j.jmb.2019.02.021

Cited by 35 publications

(29 citation statements)

References 62 publications

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“…Contact maps provide a way to identify correlated segments and characterize their stabilizing interactions. For example, it is interesting to investigate whether cation-p or other types of interactions contribute to the slow dynamics of two tryptophans in the C-terminal domain of the nucleoprotein of Sendai virus (38,48), or the precise interactions that may be responsible for the slow dynamics of two stretches of residues in HOX transcription factors (72). Accumulation of such knowledge over a large number of IDPs will advance our understanding of how amino-acid sequences of IDPs, through the formation of correlated segments, code for dynamics.…”

Section: Discussionmentioning

confidence: 99%

Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ

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et al. 2020

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Intrinsically disordered proteins (IDPs) account for a significant fraction of any proteome and are central to numerous cellular functions. Yet how sequences of IDPs code for their conformational dynamics is poorly understood. Here we combined NMR spectroscopy, small-angle X-ray scattering (SAXS), and molecular dynamics (MD) simulations to characterize the conformations and dynamics of ChiZ1-64. This IDP is the N-terminal fragment (residues 1-64) of the transmembrane protein ChiZ, a component of the cell division machinery in Mycobacterium tuberculosis. Its Nhalf contains most of the prolines and all of the anionic residues while the C-half most of the glycines and cationic residues. MD simulations, first validated by SAXS and secondary chemical shift data, found scant a-helices or b-strands but considerable propensity for polyproline II (PPII) torsion angles. Importantly, several blocks of residues (e.g., 11-29) emerge as "correlated segments", identified by frequent formation of PPII stretches, salt bridges, cation-p interactions, and sidechain-backbone hydrogen bonds. NMR relaxation experiments showed non-uniform transverse relaxation rates (R2s) and nuclear Overhauser enhancements (NOEs) along the sequence (e.g., high R2s and NOEs for residues 11-14 and 23-28). MD simulations further revealed that the extent of segmental correlation is sequence-dependent: segments where internal interactions are more prevalent manifest elevated "collective" motions on the 5-10 ns timescale and suppressed local motions on the sub-ns timescale. Amide proton exchange rates provides corroboration, with residues in the most correlated segment exhibiting the highest protection factors. We propose correlated segment as a defining feature for the conformation and dynamics of IDPs.

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Section: Discussionmentioning

confidence: 99%

Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ

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Cross

et al. 2020

Preprint

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“…One question arising from this behaviour is how interaction specificity, which allows a precise matching of Hox function and activity to the cell type and developmental stage, is achieved. It is known that Ubx protein, like many other TFs, harbours intrinsically disordered domains that are important for selecting interacting partners [63][64][65] . Thus, the few lineagerestricted Ubx interactors identified in this study, in particular Tin or Grh, could be responsible for Ubx's differential interaction potential by binding to these intrinsically disordered domains.…”

Section: Discussionmentioning

confidence: 99%

Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity

et al. 2020

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Transcription factors (TFs) control cell fates by precisely orchestrating gene expression. However, how individual TFs promote transcriptional diversity remains unclear. Here, we use the Hox TF Ultrabithorax (Ubx) as a model to explore how a single TF specifies multiple cell types. Using proximity-dependent Biotin IDentification in Drosophila, we identify Ubx interactomes in three embryonic tissues. We find that Ubx interacts with largely non-overlapping sets of proteins with few having tissue-specific RNA expression. Instead most interactors are active in many cell types, controlling gene expression from chromatin regulation to the initiation of translation. Genetic interaction assays in vivo confirm that they act strictly lineage-and process-specific. Thus, functional specificity of Ubx seems to play out at several regulatory levels and to result from the controlled restriction of the interaction potential by the cellular environment. Thereby, it challenges long-standing assumptions such as differential RNA expression as determinant for protein complexes.

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“…Case 3: The "deformed" (DFD) HOX transcription factor controls the development of the labial and prothorax segments in Drosophila 53 . A segment of DFD containing a conserved 60-residue DNA-binding homeodomain and the 30 preceding residues (T337-K426) was studied by NMR spectroscopy and other biophysical characterization techniques 54 . ODiNPred predicts the C-terminal DNA-binding domain to be ordered whereas the 30 N-terminal residues are predicted as mostly disordered (Fig.…”

Section: Evaluation Of Odinpred On Four Important Examples Of Disordementioning

confidence: 99%

“…Residues 8-11 were demonstrated to be more rigid than the remainder of the disordered N-terminal region by NMR relaxation analysis and MD simulations. This segment with reduced flexibility is specifically recognized by other co-transcription factors 54 .…”

Section: Evaluation Of Odinpred On Four Important Examples Of Disordementioning

confidence: 99%

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ODiNPred: comprehensive prediction of protein order and disorder

Dass

Mulder

Nielsen

2020

Sci Rep

162

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Structural disorder is widespread in eukaryotic proteins and is vital for their function in diverse biological processes. It is therefore highly desirable to be able to predict the degree of order and disorder from amino acid sequence. It is, however, notoriously difficult to predict the degree of local flexibility within structured domains and the presence and nuances of localized rigidity within intrinsically disordered regions. To identify such instances, we used the CheZOD database, which encompasses accurate, balanced, and continuous-valued quantification of protein (dis)order at amino acid resolution based on NMR chemical shifts. To computationally forecast the spectrum of protein disorder in the most comprehensive manner possible, we constructed the sequence-based protein order/disorder predictor ODiNPred, trained on an expanded version of CheZOD. ODiNPred applies a deep neural network comprising 157 unique sequence features to 1325 protein sequences together with the experimental NMR chemical shift data. Cross-validation for 117 protein sequences shows that ODiNPred better predicts the continuous variation in order along the protein sequence, suggesting that contemporary predictors are limited by the quality of training data. The inclusion of evolutionary features reduces the performance gap between ODiNPred and its peers, but analysis shows that it retains greater accuracy for the more challenging prediction of intermediate disorder.

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Dynamic Studies on Intrinsically Disordered Regions of Two Paralogous Transcription Factors Reveal Rigid Segments with Important Biological Functions

Cited by 35 publications

References 62 publications

Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ

Sequence-dependent correlated segments in the intrinsically disordered region of ChiZ

Multi-level and lineage-specific interactomes of the Hox transcription factor Ubx contribute to its functional specificity

ODiNPred: comprehensive prediction of protein order and disorder

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