Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE239884 | GEO | 2023/11/19
REPOSITORIES: GEO
Similar Datasets
Project description:Intrinsically disordered regions (IDRs) are abundant within eukaryotic proteins, but their sequence-function relationship remains poorly understood. IDRs of transcription factors (TFs) can direct promoter selection and recruit coactivators, as exemplified by the budding-yeast TF- Msn2. To examine how low-complexity IDRs encode multiple functions, we compared genomic binding preferences, gene induction, and coactivator recruitment amongst a large set of designed Mns2-IDR mutants. We show that multiple regions across the >500AA IDR contribute to both functions. Yet, transcription activity was readily disrupted by variants having no consequences on Msn2 binding. Our data attribute this differential sensitivity to the integration of relaxed, composition-based code directing binding preferences with a more stringent, motif-based code controlling the recruitment of coactivators and transcription activity. Interwoven sequence grammar may present a general paradigm through which low-complexity IDRs encode multiple functions.
2023-11-19 | GSE239883 | GEO
Project description:Intrinsically disordered regions (IDRs) are abundant within eukaryotic proteins, but their sequence-function relationship remains poorly understood. IDRs of transcription factors (TFs) can direct promoter selection and recruit coactivators, as exemplified by the budding-yeast TF- Msn2. To examine how low-complexity IDRs encode multiple functions, we compared genomic binding preferences, gene induction, and coactivator recruitment amongst a large set of designed Mns2-IDR mutants. We show that multiple regions across the >500AA IDR contribute to both functions. Yet, transcription activity was readily disrupted by variants having no consequences on Msn2 binding. Our data attribute this differential sensitivity to the integration of relaxed, composition-based code directing binding preferences with a more stringent, motif-based code controlling the recruitment of coactivators and transcription activity. Interwoven sequence grammar may present a general paradigm through which low-complexity IDRs encode multiple functions.
2023-11-19 | GSE239882 | GEO
Project description:Proteins and synthetic polymers that undergo aqueous phase transitions mediate self-assembly in nature and in man-made material systems. Yet little is known about how the phase behaviour of a protein is encoded in its amino acid sequence. Here, by synthesizing intrinsically disordered, repeat proteins to test motifs that we hypothesized would encode phase behaviour, we show that the proteins can be designed to exhibit tunable lower or upper critical solution temperature (LCST and UCST, respectively) transitions in physiological solutions. We also show that mutation of key residues at the repeat level abolishes phase behaviour or encodes an orthogonal transition. Furthermore, we provide heuristics to identify, at the proteome level, proteins that might exhibit phase behaviour and to design novel protein polymers consisting of biologically active peptide repeats that exhibit LCST or UCST transitions. These findings set the foundation for the prediction and encoding of phase behaviour at the sequence level.
| S-EPMC4618764 | biostudies-literature
Project description:RNA helicases—central enzymes in RNA metabolism— often feature intrinsically disordered regions (IDRs) that enable phase separation and complex interactions with other proteins and/or RNA molecules. IDRs are varied and fast evolving, which makes their function hard to predict. In the bacterial pathogen Pseudomonas aeruginosa, two non-redundant RNA helicases, RhlE1 and RhlE2, share a conserved REC catalytic core but have different C-terminal extensions (CTEs) composed of IDRs of diverse length and amino acid composition. Here, we show how the IDR diversity defines RhlE RNA helicase specificity of function. Both CTEs facilitate RNA binding and phase separation in vitro, leading to the in vivo localization of proteins in clusters within the cytoplasm. However, the CTE of RhlE2 is more efficient in enhancing REC core RNA unwinding, exhibits a greater tendency for phase separation, and interacts with the RNase E endonuclease, a crucial player in mRNA degradation. Swapping CTEs results in chimeric proteins that are biochemically active but functionally distinct as compared to their native counterparts. The RECRhlE1-CTERhlE2 chimera improves cold growth of a rhlE1 mutant, gains interaction with RNase E and affects a subset of both RhlE1 and RhlE2 RNA targets. The RECRhlE2-CTERhlE1 chimera instead hampers bacterial growth at low temperatures in the absence of RhlE1, with its detrimental effect linked to aberrant RNA droplets. By showing that IDRs modulate both protein core activities and subcellular localization, our study defines the impact of IDR diversity on the functional differentiation of RNA helicases.
2024-05-30 | GSE253333 | GEO
Project description:An amyloidogenic region (AR) in a protein sequence plays a significant role in protein aggregation and amyloid formation. We have investigated the sequence complexity of AR that is present in intrinsically disordered human proteins. More than 80% human proteins in the disordered protein databases (DisProt+IDEAL) contained one or more ARs. With decrease of protein disorder, AR content in the protein sequence was decreased. A probability density distribution analysis and discrete analysis of AR sequences showed that ∼8% residue in a protein sequence was in AR and the region was in average 8 residues long. The residues in the AR were high in sequence complexity and it seldom overlapped with low complexity regions (LCR), which was largely abundant in disorder proteins. The sequences in the AR showed mixed conformational adaptability towards α-helix, β-sheet/strand and coil conformations.
| S-EPMC3940659 | biostudies-literature
Project description:Autophagy is an essential eukaryotic pathway required for cellular homeostasis. Numerous key autophagy effectors and regulators have been identified, but the mechanism by which they carry out their function in autophagy is not fully understood. Our rigorous bioinformatic analysis shows that the majority of key human autophagy proteins include intrinsically disordered regions (IDRs), which are sequences lacking stable secondary and tertiary structure; suggesting that IDRs play an important, yet hitherto uninvestigated, role in autophagy. Available crystal structures corroborate the absence of structure in some of these predicted IDRs. Regions of orthologs equivalent to the IDRs predicted in the human autophagy proteins are poorly conserved, indicating that these regions may have diverse functions in different homologs. We also show that IDRs predicted in human proteins contain several regions predicted to facilitate protein-protein interactions, and delineate the network of proteins that interact with each predicted IDR-containing autophagy protein, suggesting that many of these interactions may involve IDRs. Lastly, we experimentally show that a BCL2 homology 3 domain (BH3D), within the key autophagy effector BECN1 is an IDR. This BH3D undergoes a dramatic conformational change from coil to ?-helix upon binding to BCL2s, with the C-terminal half of this BH3D constituting a binding motif, which serves to anchor the interaction of the BH3D to BCL2s. The information presented here will help inform future in-depth investigations of the biological role and mechanism of IDRs in autophagy proteins.
| S-EPMC3949125 | biostudies-literature
Project description:BACKGROUND:Molecular Recognition Features (MoRFs) are short protein regions present in intrinsically disordered protein (IDPs) sequences. MoRFs interact with structured partner protein and upon interaction, they undergo a disorder-to-order transition to perform various biological functions. Analyses of MoRFs are important towards understanding their function. RESULTS:Performance is reported using the MoRF dataset that has been previously used to compare the other existing MoRF predictors. The performance obtained in this study is equivalent to the benchmarked OPAL predictor, i.e., OPAL achieved AUC of 0.815, whereas the model in this study achieved AUC of 0.819 using TEST set. CONCLUSION:Achieving comparable performance, the proposed method can be used as an alternative approach for MoRF prediction.
| S-EPMC7653905 | biostudies-literature
Project description:Phosphorylation is a major post-translational modification that plays a central role in signaling pathways. Protein kinases phosphorylate substrates (phosphoproteins) by adding phosphate at Ser/Thr or Tyr residues (phosphosites). A large amount of data identifying and describing phosphosites in phosphoproteins has been reported but the specificity of phosphorylation is not fully resolved. In this report, data of kinase-substrate pairs identified by the Kinase-Interacting Substrate Screening (KISS) method were used to analyze phosphosites in intrinsically disordered regions (IDRs) of intrinsically disordered proteins. We compared phosphorylated and nonphosphorylated IDRs and found that the phosphorylated IDRs were significantly longer than nonphosphorylated IDRs. The phosphorylated IDR is often the longest IDR (71%) in a phosphoprotein when only a single phosphosite exists in the IDR, and when the phosphoprotein has multiple phosphosites in an IDR(s), the phosphosites are primarily localized in a single IDR (78%) and this IDR is usually the longest one (81%). We constructed a stochastic model of phosphorylation to estimate the effect of IDR length. The model that accounted for IDR length produced more realistic results when compared with a model that excluded the IDR length. We propose that the IDR length is a significant determinant for locating kinase phosphorylation sites in phosphoproteins.
| S-EPMC6954741 | biostudies-literature
Project description:With the exponential increase in the number of sequenced organisms, automated annotation of proteins is becoming increasingly important. Intrinsically disordered regions are known to play a significant role in protein function. Despite their abundance, especially in eukaryotes, they are rarely used to inform function prediction systems. In this study, we extracted seven sequence features in intrinsically disordered regions and developed a scheme to use them to predict Gene Ontology Slim terms associated with proteins. We evaluated the function prediction performance of each feature. Our results indicate that the residue composition based features have the highest precision while bigram probabilities, based on sequence profiles of intrinsically disordered regions obtained from PSIBlast, have the highest recall. Amino acid bigrams and features based on secondary structure show an intermediate level of precision and recall. Almost all features showed a high prediction performance for GO Slim terms related to extracellular matrix, nucleus, RNA and DNA binding. However, feature performance varied significantly for different GO Slim terms emphasizing the need for a unique classifier optimized for the prediction of each functional term. These findings provide a first comprehensive and quantitative evaluation of sequence features in intrinsically disordered regions and will help in the development of a more informative protein function predictor.
| S-EPMC3933697 | biostudies-literature
Project description:Forkhead box Class O is one of 19 subfamilies of the Forkhead box family, comprising 4 human transcription factors: FOXO1, FOXO3a, FOXO4, and FOXO6, which are involved in many crucial cellular processes. FOXO3a is a tumor suppressor involved in multiple physiological and pathological processes, and plays essential roles in metabolism, cell cycle arrest, DNA repair, and apoptosis. In its role as a transcription factor, the FOXO3a binds a consensus Forkhead response element DNA sequence, and recruits transcriptional coactivators to activate gene transcription. FOXO3a has additional functions, such as regulating p53-mediated apoptosis and activating kinase ATM. With the exception of the structured DNA-binding forkhead domain, most of the FOXO3a sequence comprises intrinsically disordered regions (IDRs), including 3 regions (CR1-3) that are conserved within the FOXO subfamily. Numerous studies have demonstrated that these IDRs directly mediate many of the diverse functions of FOXO3a. These regions contain post-translational modification and protein-protein interaction sites that integrate upstream signals to maintain homeostasis. Thus, the FOXO3a IDRs are emerging as key mediators of diverse regulatory processes, and represent an important target for the future development of therapeutics for FOXO3a-related diseases.
| S-EPMC5314938 | biostudies-literature