The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

Babu, M. Madan

doi:10.1042/bst20160172

Cited by 317 publications

(304 citation statements)

References 160 publications

Supporting

Mentioning

294

Contrasting

Order By: Relevance

“…TF ADs have been classified by their amino acid profile as acidic, proline-rich, serine/threonine-rich, glutamine-rich, or by their hypothetical shape as acid blobs, negative noodles, or peptide lassos (Sigler, 1988). Many of these features have been described for IDRs that are capable of forming phase-separated condensates (Babu, 2016; Darling et al, 2018; Das et al, 2015; Dunker et al, 2015; Habchi et al, 2014; van der Lee et al, 2014; Oldfield and Dunker, 2014; Uversky, 2017; Wright and Dyson, 2015). Evidence that the GCN4 AD interacts with MED15 in multiple orientations and conformations to form a “fuzzy complex” (Tuttle et al, 2018) is consistent with the notion of dynamic low-affinity interactions characteristic of phase-separated condensates.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Boija

Klein

Sabari

et al. 2018

Cell

1,281

1,301

View full text Add to dashboard Cite

Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well-characterized, but little is known about the mechanisms by which ADs effect gene activation. Here we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation.

show abstract

Section: Discussionmentioning

confidence: 99%

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Boija

Klein

Sabari

et al. 2018

Cell

1,281

1,301

View full text Add to dashboard Cite

show abstract

“…Since IDPs typically contain motifs that mediate multiple molecular interactions, they are commonly associated with signaling pathways and have recently been linked to a number of human diseases (Babu, 2016). This is emphasized by a bioinformatics study of transcription factors that showed that extended regions of disorder are common in the regulatory domains (Liu et al, 2006).…”

Section: Versatility Of the Maab Pipeline For Hrgpsmentioning

confidence: 99%

“…Intrinsically disordered proteins (IDPs) challenge the traditional view that proteins fold into a fixed threedimensional structure that determines their function (Babu, 2016). IDPs do not conform to the structurefunction paradigm, as they are highly mobile, lack a persistent structure, and yet are stable (Schlessinger et al, 2011;Szalkowski and Anisimova, 2011;FormanKay and Mittag, 2013;Light et al, 2013).…”

mentioning

confidence: 99%

Pipeline to Identify Hydroxyproline-Rich Glycoproteins

et al. 2017

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) are functional proteins that lack a well-defined three-dimensional structure. The study of IDPs is a rapidly growing area as the crucial biological functions of more of these proteins are uncovered. In plants, IDPs are implicated in plant stress responses, signaling, and regulatory processes. A superfamily of cell wall proteins, the hydroxyprolinerich glycoproteins (HRGPs), have characteristic features of IDPs. Their protein backbones are rich in the disordering amino acid proline, they contain repeated sequence motifs and extensive posttranslational modifications (glycosylation), and they have been implicated in many biological functions. HRGPs are evolutionarily ancient, having been isolated from the protein-rich walls of chlorophyte algae to the cellulose-rich walls of embryophytes. Examination of HRGPs in a range of plant species should provide valuable insights into how they have evolved. Commonly divided into the arabinogalactan proteins, extensins, and proline-rich proteins, in reality, a continuum of structures exists within this diverse and heterogenous superfamily. An inability to accurately classify HRGPs leads to inconsistent gene ontologies limiting the identification of HRGP classes in existing and emerging omics data sets. We present a novel and robust motif and amino acid bias (MAAB) bioinformatics pipeline to classify HRGPs into 23 descriptive subclasses. Validation of MAAB was achieved using available genomic resources and then applied to the 1000 Plants transcriptome project (www.onekp.com) data set. Significant improvement in the detection of HRGPs using multiple-kmer transcriptome assembly methodology was observed. The MAAB pipeline is readily adaptable and can be modified to optimize the recovery of IDPs from other organisms.

show abstract

“…Indeed, the massive expansions of transcription factor (TF) families containing significant amounts of IDRs in complex organisms has been used as evidence that IDRs and their alternative splicing and posttranslational modification have been a driving force in the evolution of complex multicellularity (Niklas et al 2014, 2015; Niklas and Dunker 2016; Dunker et al 2015; Babu 2016). This proposition is supported by disorder predictions showing that 83–94% of all known TFs possess extended regions of disordered residues and that the degree of intrinsic disorder is significantly higher in eukaryotic than in prokaryotic TFs (Liu et al 2006; Minezaki et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity

Yruela

Oldfield

Niklas

et al. 2017

Genome Biology and Evolution

View full text Add to dashboard Cite

Studies of diverse phylogenetic lineages reveal that protein disorder increases in concert with organismic complexity but that differences nevertheless exist among lineages. To gain insight into this phenomenology, we analyzed all of the transcription factor (TF) families for which sequences are known for 17 species spanning bacteria, yeast, algae, land plants, and animals and for which the number of different cell types has been reported in the primary literature. Although the fraction of disordered residues in TF sequences is often moderately or poorly correlated with organismic complexity as gauged by cell-type number (r2 < 0.5), an unbiased and phylogenetically broad analysis shows that organismic complexity is positively and strongly correlated with the total number of TFs, the number of their spliced variants and their total disordered residues content (r2 > 0.8). Furthermore, the correlation between the fraction of disordered residues and cell-type number becomes stronger when confined to the TF families participating in cell cycle, cell size, cell division, cell differentiation, or cell proliferation, and other important developmental processes. The data also indicate that evolutionarily simpler organisms allow for the detection of subtle differences in the conserved IDRs of TFs as well as changes in variable IDRs, which can influence the DNA recognition and multifunctionality of TFs through direct or indirect mechanisms. Although strong correlations cannot be taken as evidence for cause-and-effect relationships, we interpret our data to indicate that increasing TF disorder likely was an important factor contributing to the evolution of organismic complexity and not merely a concurrent unrelated effect of increasing organismic complexity.

show abstract

The contribution of intrinsically disordered regions to protein function, cellular complexity, and human disease

Cited by 317 publications

References 160 publications

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Pipeline to Identify Hydroxyproline-Rich Glycoproteins

Evidence for a Strong Correlation Between Transcription Factor Protein Disorder and Organismic Complexity

Contact Info

Product

Resources

About