scholarly journals The Significance of the Intrinsically Disordered Regions for the Functions of the bHLH Transcription Factors

2019 ◽  
Vol 20 (21) ◽  
pp. 5306 ◽  
Author(s):  
Aneta Tarczewska ◽  
Beata Greb-Markiewicz
Keyword(s):  
Transcription Factors ◽  
Phase Separation ◽  
Transcription Regulation ◽  
Experimental Studies ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Bhlh Transcription Factors ◽  
Bhlh Proteins ◽  
Disordered Regions

The bHLH proteins are a family of eukaryotic transcription factors regulating expression of a wide range of genes involved in cell differentiation and development. They contain the Helix-Loop-Helix (HLH) domain, preceded by a stretch of basic residues, which are responsible for dimerization and binding to E-box sequences. In addition to the well-preserved DNA-binding bHLH domain, these proteins may contain various additional domains determining the specificity of performed transcriptional regulation. According to this, the family has been divided into distinct classes. Our aim was to emphasize the significance of existing disordered regions within the bHLH transcription factors for their functionality. Flexible, intrinsically disordered regions containing various motives and specific sequences allow for multiple interactions with transcription co-regulators. Also, based on in silico analysis and previous studies, we hypothesize that the bHLH proteins have a general ability to undergo spontaneous phase separation, forming or participating into liquid condensates which constitute functional centers involved in transcription regulation. We shortly introduce recent findings on the crucial role of the thermodynamically liquid-liquid driven phase separation in transcription regulation by disordered regions of regulatory proteins. We believe that further experimental studies should be performed in this field for better understanding of the mechanism of gene expression regulation (among others regarding oncogenes) by important and linked to many diseases the bHLH transcription factors.

scholarly journals The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

2021 ◽  
Vol 22 (6) ◽  
pp. 2868
Author(s):  
Marta Kolonko-Adamska ◽  
Vladimir N. Uversky ◽  
Beata Greb-Markiewicz
Keyword(s):  
Transcription Factors ◽  
Phase Separation ◽  
Posttranslational Modifications ◽  
Wide Spectrum ◽  
In Silico Analysis ◽  
Missense Mutations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

The basic helix–loop–helix/Per-ARNT-SIM (bHLH-PAS) proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, ranging from differentiation and development control by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for regulation of their activity. Our aim was to analyze the potential connection between disordered regions of the bHLH-PAS transcription factors, post-transcriptional modifications and liquid-liquid phase separation, in the context of disease-associated missense mutations. Highly flexible disordered regions, enriched in short motives which are more ordered, are responsible for a wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account the fact that the functions of transcription factors can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the locations of missense mutations inducing disease states are clearly related to sequences directly undergoing these processes or to sequences responsible for their regulation.

scholarly journals The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

2020 ◽  
Author(s):  
Beata Greb-Markiewicz ◽  
Marta Kolonko-Adamska
Keyword(s):  
Transcription Factors ◽  
Phase Separation ◽  
Wide Spectrum ◽  
In Silico Analysis ◽  
Activity Regulation ◽  
Missense Mutations ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

The bHLH-PAS proteins are a family of transcription factors regulating expression of a wide range of genes involved in different functions, from differentiation and development control, by oxygen and toxins sensing to circadian clock setting. In addition to the well-preserved DNA-binding bHLH and PAS domains, bHLH-PAS proteins contain long intrinsically disordered C-terminal regions, responsible for their activity regulation. Our aim was to analyse the potential connection between disordered regions of the bHLH-PAS transcription factors with posttranscriptional modifications and liquid-liquid phase separation in the context of the disease-associated missense mutations. Highly flexible disordered regions, enriched in short more ordered motives, are responsible for wide spectrum of interactions with transcriptional co-regulators. Based on our in silico analysis and taking into account fact that transcription factors functions can be modulated by posttranslational modifications and spontaneous phase separation, we assume that the location of missense mutations inducing disease states, is clearly related to sequences directly undergoing these processes or to sequences responsible for their activity regulation.

scholarly journals Atoh8 in Development and Disease

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 136
Author(s):  
Satya Srirama Karthik Divvela ◽  
Darius Saberi ◽  
Beate Brand-Saberi
Keyword(s):  
Transcription Factors ◽  
Embryonic Development ◽  
Subcellular Location ◽  
Transcriptional Regulators ◽  
Special Group ◽  
Helix Loop Helix ◽  
Wide Range ◽  
Disease Initiation ◽  
Bhlh Transcription Factors ◽  
Bhlh Proteins

Atoh8 belongs to a large superfamily of transcriptional regulators called basic helix-loop-helix (bHLH) proteins. bHLH proteins have been identified in a wide range of organisms from yeast to humans. The members of this special group of transcription factors were found to be involved not only in embryonic development but also in disease initiation and its progression. Given their importance in several fundamental processes, the translation, subcellular location and turnover of bHLH proteins is tightly regulated. Alterations in the expression of bHLH proteins have been associated with multiple diseases also in context with Atoh8 which seems to unfold its functions as both transcriptional activator and repressor. Like many other bHLH transcription factors, so far, Atoh8 has also been observed to be involved in both embryonic development and carcinogenesis where it mainly acts as tumor suppressor. This review summarizes our current understanding of Atoh8 structure, function and regulation and its complex and partially controversial involvement in development and disease.

scholarly journals Proteome-scale amino-acid resolution footprinting of protein-binding sites in the intrinsically disordered regions of the human proteome

2021 ◽  
Author(s):  
Caroline Benz ◽  
Muhammad Ali ◽  
Izabella Krystkowiak ◽  
Leandro Simonetti ◽  
Ahmed Sayadi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Human Proteome ◽  
Cell Physiology ◽  
Protein Protein Interactions ◽  
Linear Motif ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Wide Range ◽  
Disordered Regions

Specific protein-protein interactions are central to all processes that underlie cell physiology. Numerous studies using a wide range of experimental approaches have identified tens of thousands of human protein-protein interactions. However, many interactions remain to be discovered, and low affinity, conditional and cell type-specific interactions are likely to be disproportionately under-represented. Moreover, for most known protein-protein interactions the binding regions remain uncharacterized. We previously developed proteomic peptide phage display (ProP-PD), a method for simultaneous proteome-scale identification of short linear motif (SLiM)-mediated interactions and footprinting of the binding region with amino acid resolution. Here, we describe the second-generation human disorderome (HD2), an optimized ProP-PD library that tiles all disordered regions of the human proteome and allows the screening of ~1,000,000 overlapping peptides in a single binding assay. We define guidelines for how to process, filter and rank the results and provide PepTools, a toolkit for annotation and analysis of identified hits. We uncovered 2,161 interaction pairs for 35 known SLiM-binding domains and confirmed a subset of 38 interactions by biophysical or cell-based assays. Finally, we show how the amino acid resolution binding site information can be used to pinpoint functionally important disease mutations and phosphorylation events in intrinsically disordered regions of the human proteome. The HD2 ProP-PD library paired with PepTools represents a powerful pipeline for unbiased proteome-wide discovery of SLiM-based interactions.

scholarly journals Pi-Pi contacts are an overlooked protein feature relevant to phase separation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Robert McCoy Vernon ◽  
Paul Andrew Chong ◽  
Brian Tsang ◽  
Tae Hun Kim ◽  
Alaji Bah ◽  
...  
Keyword(s):  
Phase Separation ◽  
Hydrophobic Effect ◽  
Nuclear Pore ◽  
Regular Secondary Structure ◽  
Predictive Algorithm ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Folded Proteins ◽  
Pi Interactions ◽  
Disordered Regions

Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore. Multivalent interactions of modular binding domains and their target motifs can drive phase separation. However, forces promoting the more common phase separation of intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi-pi, and charge interactions and the hydrophobic effect. Known phase-separating proteins are enriched in pi-orbital containing residues and thus we analyzed pi-interactions in folded proteins. We found that pi-pi interactions involving non-aromatic groups are widespread, underestimated by force-fields used in structure calculations and correlated with solvation and lack of regular secondary structure, properties associated with disordered regions. We present a phase separation predictive algorithm based on pi interaction frequency, highlighting proteins involved in biomaterials and RNA processing.

scholarly journals Interaction between intrinsically disordered regions in transcription factors Sp1 and TAF4

2016 ◽  
Vol 25 (11) ◽  
pp. 2006-2017 ◽  
Author(s):  
Emi Hibino ◽  
Rintaro Inoue ◽  
Masaaki Sugiyama ◽  
Jun Kuwahara ◽  
Katsumi Matsuzaki ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Disordered Regions
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