The two interfaces of the STAT1 N-terminus exhibit opposite functions in IFNγ-regulated gene expression

Staab, Julia; Riebeling, Theresa; Koch, Verena; Herrmann‐Lingen, Christoph; Meyer, Thomas

doi:10.1016/j.molimm.2015.07.015

Cited by 3 publications

(3 citation statements)

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“…Oligomerization can also switch the function of a given protein. Remarkably, transcription factors use dimerization and oligomerization as a way to not only increase their affinity for DNA [ 18 , 19 , 20 , 21 , 22 ] ( Figure 1 B) but also to modulate the subset of genes to be regulated [ 23 , 24 , 25 , 26 ] or vary the binding partners that can be recruited [ 27 , 28 ]. For example, for transcription factors involved in circadian oscillations, variation in their oligomeric status is a simple and efficient way to modulate activity [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

Gambin

Polinkovsky

François

et al. 2016

IJMS

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Protein self-association is a key feature that can modulate the physiological role of proteins or lead to deleterious effects when uncontrolled. Protein oligomerization is a simple way to modify the activity of a protein, as the modulation of binding interfaces allows for self-activation or inhibition, or variation in the selectivity of binding partners. As such, dimerization and higher order oligomerization is a common feature in signaling proteins, for example, and more than 70% of enzymes have the potential to self-associate. On the other hand, protein aggregation can overcome the regulatory mechanisms of the cell and can have disastrous physiological effects. This is the case in a number of neurodegenerative diseases, where proteins, due to mutation or dysregulation later in life, start polymerizing and often fibrillate, leading to the creation of protein inclusion bodies in cells. Dimerization, well-defined oligomerization and random aggregation are often difficult to differentiate and characterize experimentally. Single molecule “counting” methods are particularly well suited to the study of self-oligomerization as they allow observation and quantification of behaviors in heterogeneous conditions. However, the extreme dilution of samples often causes weak complexes to dissociate, and rare events can be overlooked. Here, we discuss a straightforward alternative where the principles of single molecule detection are used at higher protein concentrations to quantify oligomers and aggregates in a background of monomers. We propose a practical guide for the use of confocal spectroscopy to quantify protein oligomerization status and also discuss about its use in monitoring changes in protein aggregation in drug screening assays.

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Section: Introductionmentioning

confidence: 99%

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

Gambin

Polinkovsky

François

et al. 2016

IJMS

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“…1 C, D). In a previous publication, we identified N-terminal point mutations, which displayed altered DNA binding, leading to a hyperactive phenotype [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

A novel interface between the N-terminal and coiled-coil domain of STAT1 functions in an auto-inhibitory manner

Remling,

Gregus,

Wirths

et al. 2023

Cell Commun Signal

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Background STAT1 is an intracellular signaling molecule that is crucially involved in the regulation of the innate immune system by activation of defense mechanisms against microbial pathogens. Phosphorylation-dependent activation of the STAT1 transcription factor is associated with a conversion from an antiparallel to parallel dimer configuration, which after nuclear import binds to DNA. However, not much is known about the specific intermolecular interactions that stabilize unphosphorylated, antiparallel STAT1 complexes prior to activation. Results In this study, we identified a previously unknown interdimeric interaction site, which is involved in the termination of STAT1 signaling. Introduction of the glutamic acid-to-alanine point mutation E169A in the coiled-coil domain (CCD) by site-directed mutagenesis led to increased tyrosine phosphorylation as well as accelerated and prolonged nuclear accumulation in transiently transfected cells. In addition, DNA-binding affinity and transcriptional activity were strongly enhanced in the substitution mutant compared to the wild-type (WT) protein. Furthermore, we have demonstrated that the E169 residue in the CCD mediates the release of the dimer from the DNA in an auto-inhibitory manner. Conclusion Based on these findings, we propose a novel mechanism for the inactivation of the STAT1 signaling pathway, assigning the interface with the glutamic acid residue 169 in the CCD a crucial role in this process.

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“…On the basis of the observation that mutations on the surface of NDD affect the stability of the tetramer complex, Staab et al[ 18 ] recently suggested a model of the tetramer complex in which the two core dimers are arranged in an eclipsed state and connected by one on-axis NDD sitting close to the DNA. Our calculations show that a model of this type is possible (although possible positions of NDD are not in the ‘front’ but on the ‘backside’ of DNA in between the SH2 domains, see Fig 4C and 4D ) but is associated with a low feasibility measure.…”

Section: Discussionmentioning

confidence: 99%

Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative Genome-Wide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites

2016

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STAT proteins bind DNA as dimers and tetramers to control cellular development, differentiation, survival, and expansion. The tetramer binding sites are comprised of two dimer-binding sites repeated in tandem. The genome-wide distribution of the spacings between the dimer binding sites shows a distinctive, non-random pattern. Here, we report on estimating the feasibility of building possible molecular models of STAT5A tetramers bound to a DNA double helix with all possible spacings between the dimer binding sites. We found that the calculated feasibility estimates correlated well with the experimentally measured frequency of tetramer-binding sites. This suggests that the feasibility of forming the tetramer complex was a major factor in the evolution of this DNA sequence variation.

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The two interfaces of the STAT1 N-terminus exhibit opposite functions in IFNγ-regulated gene expression

Cited by 3 publications

References 39 publications

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

Confocal Spectroscopy to Study Dimerization, Oligomerization and Aggregation of Proteins: A Practical Guide

A novel interface between the N-terminal and coiled-coil domain of STAT1 functions in an auto-inhibitory manner

Molecular Models of STAT5A Tetramers Complexed to DNA Predict Relative Genome-Wide Frequencies of the Spacing between the Two Dimer Binding Motifs of the Tetramer Binding Sites

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