Biology subjects

Morgunova, E.

Publications and source records attributed to Morgunova, E..

4 recordsLinked to original sources

bioRxiv2023

Interfacial water confers transcription factors with dinucleotide specificity

Transcription factors bind to DNA by recognizing specific bases within their binding motifs. Binding to each DNA mononucleotide within the motif often contributes independently to total binding energy. However, some transcription factors (TFs) can bind to DNA more specifically than predicted by this model, by directly recognizing DNA dinucleotides. To understand this process, we have solved the structures of the basic helix-loop-helix protein MYF5, and the homeodomain protein BARHL2 together with DNA containing a set of dinucleotides that have different affinities to the proteins at high resolution (< 1 [A]). We observe that dinucleotides can be recognized either enthalpically by an extensive water network that connects the adjacent bases to the TF, or entropically by formation of a hydrophobic patch that maintains water mobility at the protein-DNA interface. The two distinct thermodynamic signatures of the two equally optimal sites also confer differential temperature sensitivity to the optimal sites, with implications for thermal regulation of gene expression. Our results uncover the enigma of how TFs can recognize more complex local features than mononucleotides, and demonstrate that water-mediated recognition is important in predicting affinities of macromolecules from their sequence.

biochemistry↗

bioRxiv2023

DNA-guided transcription factor cooperativity shapes face and limb mesenchyme

Transcription factors (TFs) can define distinct cellular identities despite nearly identical DNA-binding specificities. One mechanism for achieving regulatory specificity is DNA-guided TF cooperativity. Although in vitro studies suggest it may be common, examples of such cooperativity remain scarce in cellular contexts. Here, we demonstrate how Coordinator, a long DNA motif comprised of common motifs bound by many basic helix-loop-helix (bHLH) and homeodomain (HD) TFs, uniquely defines regulatory regions of embryonic face and limb mesenchyme. Coordinator guides cooperative and selective binding between the bHLH family mesenchymal regulator TWIST1 and a collective of HD factors associated with regional identities in the face and limb. TWIST1 is required for HD binding and open chromatin at Coordinator sites, while HD factors stabilize TWIST1 occupancy at Coordinator and titrate it away from HD-independent sites. This cooperativity results in shared regulation of genes involved in cell-type and positional identities, and ultimately shapes facial morphology and evolution.

genomics↗

bioRxiv2018

Characterization of novel TMEM173 mutation with additive IFIH1 risk allele

TMEM173 encodes for STING that is a transmembrane protein activated by pathogen or self-derived cytosolic nucleic acids causing its translocation from ER to Golgi, and further to vesicles. Monogenic STING gain-of-function mutations cause early-onset type I interferonopathy, with disease presentation ranging from fatal vasculopathy to mild chilblain lupus. Molecular mechanisms causing the poor phenotypegenotype correlation are presently unclear. Here we report a novel gain-of-function G207E STING mutation causing a distinct phenotype with alopecia, photosensitivity, thyroid dysfunction, and STING-associated vasculopathy with onset in infancy (SAVI) -features; livedo reticularis, nasal septum perforation, facial erythema, bacterial infections and skin vasculitis. Single residue polymorphisms in TMEM173 and an IFIH1 T946 risk allele modify disease presentation in the affected multigeneration family, explaining the varying clinical phenotypes. The G207E mutation causes constitutive activation of inflammation-related pathways in HEK cells, as well as aberrant interferon signature and inflammasome activation in patient PBMCs. Protein-protein interactions further propose impaired cellular trafficking of G207E mutant STING. These findings reveal the molecular landscape of STING and highlight the complex additive effects on the phenotype.\n\nBRIEF SUMMARYNovel gain-of-function mutation in TMEM173, associated with single residue polymorphisms in TMEM173 and IFIH1, causes a distinct clinical phenotype with some shared features of SAVI.

immunology↗

bioRxiv2017

Two distinct DNA sequences recognized by transcription factors represent enthalpy and entropy optima

Most transcription factors (TFs) can bind to a population of sequences closely related to a single optimal site. However, some TFs can bind to two distinct sequences that represent two local optima in the Gibbs free energy of binding ({Delta}G). To determine the molecular mechanism behind this effect, we solved the structures of human HOXB13 and CDX2 bound to their two optimal DNA sequences, CAATAAA and TCGTAAA. Thermodynamic analyses by isothermal titration calorimetry revealed that both sites were bound with similar {Delta}G. However, the interaction with the CAA sequence was driven by change in enthalpy ({Delta}H), whereas the TCG site was bound with similar affinity due to smaller loss of entropy ({Delta}S). The common presence of at least two local optima is general to all macromolecular interactions, as {Delta}G depends on two partially independent variables {Delta}H and {Delta}S according to the central equation of thermodynamics, {Delta}G = {Delta}H - T{Delta}S.

biochemistry↗