Intrinsically unstructured proteins by design-electrostatic interactions can control binding, folding, and function of a helix-loop-helix heterodimer

asense is a member of the achaete-scute complex (AS-C) of helix-loop-helix genes involved in Drosophila neurogenesis. Unlike the other AS-C members, which are expressed in subsets of the ectodermal areas (proneural clusters) that give rise to neural precursors, asense is one of a number of genes that are specifically expressed in the neural precursors themselves (neural precursor genes). We have identified a mutant asense phenotype that may reflect this later expression pattern. As a step in understanding the determination of neural precursors from the proneural clusters, we have investigated the potential role of the AS-C products as direct transcriptional activators of neural precursor genes by analysing the regulation of asense. Using genomic rescues and asense-lacZ fusion genes, the neural precursor regulatory element has been identified. We show that this element contains binding sites for AS-C/daughterless heterodimers. Delection of these sites reduces the expression from the fusion gene, but significant expression is still achieved, pointing to the existence of other regulators of asense in addition to the AS-C. asense differs from the other AS-C members in its expression pattern, regulation, mutant phenotype and some DNA-binding properities.

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The Crosstalk between Acetylation and Phosphorylation: Emerging New Roles for HDAC Inhibitors in the Heart

International Journal of Molecular Sciences ◽

10.3390/ijms20010102 ◽

2018 ◽

Vol 20 (1) ◽

pp. 102 ◽

Cited By ~ 9

Author(s):

Justine Habibian ◽

Bradley Ferguson

Keyword(s):

Gene Expression ◽

Protein Phosphorylation ◽

Cross Talk ◽

Electrostatic Interactions ◽

Regulation Of Gene Expression ◽

Hdac Inhibitors ◽

Protein Activity ◽

Histone Protein ◽

Signal Transduction Protein ◽

And Function

Approximately five million United States (U.S.) adults are diagnosed with heart failure (HF), with eight million U.S. adults projected to suffer from HF by 2030. With five-year mortality rates following HF diagnosis approximating 50%, novel therapeutic treatments are needed for HF patients. Pre-clinical animal models of HF have highlighted histone deacetylase (HDAC) inhibitors as efficacious therapeutics that can stop and potentially reverse cardiac remodeling and dysfunction linked with HF development. HDACs remove acetyl groups from nucleosomal histones, altering DNA-histone protein electrostatic interactions in the regulation of gene expression. However, HDACs also remove acetyl groups from non-histone proteins in various tissues. Changes in histone and non-histone protein acetylation plays a key role in protein structure and function that can alter other post translational modifications (PTMs), including protein phosphorylation. Protein phosphorylation is a well described PTM that is important for cardiac signal transduction, protein activity and gene expression, yet the functional role for acetylation-phosphorylation cross-talk in the myocardium remains less clear. This review will focus on the regulation and function for acetylation-phosphorylation cross-talk in the heart, with a focus on the role for HDACs and HDAC inhibitors as regulators of acetyl-phosphorylation cross-talk in the control of cardiac function.

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Primary Contact Sites in Intrinsically Unstructured Proteins: The Case of Calpastatin and Microtubule-Associated Protein 2†

Biochemistry ◽

10.1021/bi047817f ◽

2005 ◽

Vol 44 (10) ◽

pp. 3955-3964 ◽

Cited By ~ 75

Author(s):

Veronika Csizmók ◽

Mónika Bokor ◽

Péter Bánki ◽

Éva Klement ◽

Katalin F. Medzihradszky ◽

...

Keyword(s):

Contact Sites ◽

Primary Contact ◽

Intrinsically Unstructured Proteins ◽

Unstructured Proteins

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Coarse-grained dynamic RNA titration simulations

Interface Focus ◽

10.1098/rsfs.2018.0066 ◽

2019 ◽

Vol 9 (3) ◽

pp. 20180066 ◽

Cited By ~ 2

Author(s):

S. Pasquali ◽

E. Frezza ◽

F. L. Barroso da Silva

Keyword(s):

Electrostatic Interactions ◽

Molecular Organization ◽

Coarse Grained ◽

Solution Ph ◽

Dynamic Simulations ◽

Rna Molecules ◽

Coarse Grained Model ◽

Constant Ph ◽

Conformational Plasticity ◽

And Function

Electrostatic interactions play a pivotal role in many biomolecular processes. The molecular organization and function in biological systems are largely determined by these interactions. Owing to the highly negative charge of RNA, the effect is expected to be more pronounced in this system. Moreover, RNA base pairing is dependent on the charge of the base, giving rise to alternative secondary and tertiary structures. The equilibrium between uncharged and charged bases is regulated by the solution pH, which is therefore a key environmental condition influencing the molecule’s structure and behaviour. By means of constant-pH Monte Carlo simulations based on a fast proton titration scheme, coupled with the coarse-grained model HiRE-RNA, molecular dynamic simulations of RNA molecules at constant pH enable us to explore the RNA conformational plasticity at different pH values as well as to compute electrostatic properties as local p K a values for each nucleotide.

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Structure and function of helix-loop-helix proteins

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression ◽

10.1016/0167-4781(94)90001-9 ◽

1994 ◽

Vol 1218 (2) ◽

pp. 129-135 ◽

Cited By ~ 299

Author(s):

Cornelis Murre ◽

Gretchen Bain ◽

Marc A. van Dijk ◽

Isaac Engel ◽

Beth A. Furnari ◽

...

Keyword(s):

Structure And Function ◽

Helix Loop Helix ◽

And Function

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Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP

Biochemical Journal ◽

10.1042/bj20071156 ◽

2008 ◽

Vol 411 (2) ◽

pp. 261-270 ◽

Cited By ~ 28

Author(s):

Nikolas G. Tsatsos ◽

Michael N. Davies ◽

Brennon L. O'callaghan ◽

Howard C. Towle

Keyword(s):

Transcription Factor ◽

High Glucose ◽

Leucine Zipper ◽

De Novo ◽

Regulatory Region ◽

De Novo Lipogenesis ◽

Nuclear Accumulation ◽

Helix Loop Helix ◽

Genes Encoding ◽

And Function

In the liver, induction of genes encoding enzymes involved in de novo lipogenesis occurs in response to increased glucose metabolism. ChREBP (carbohydrate-response-element-binding protein) is a basic helix–loop–helix/leucine zipper transcription factor that regulates expression of these genes. To evaluate the potential role of ChREBP phosphorylation in its regulation, we used MS to identify modified residues. In the present paper, we report the detection of multiple phosphorylation sites of ChREBP expressed in hepatocytes, several of which are only observed under high-glucose conditions. Mutation of each of these serine/threonine residues of ChREBP did not alter its ability to respond to glucose. However, mutation of five N-terminal phosphoacceptor sites resulted in a major decrease in activity under high-glucose conditions. These phosphorylated residues are located within a region of ChREBP (amino acids 1–197) that is critical for glucose regulation. Mutation of Ser56 within this region to an aspartate residue resulted in increased nuclear accumulation and activity under high-glucose conditions. Together, these data suggest that ChREBP activity is regulated by complex multisite phosphorylation patterns involving its N-terminal regulatory region.

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