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Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE239884 | GEO | 2023/11/19

REPOSITORIES: GEO

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Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars.

Project description:Intrinsically disordered regions (IDRs) are abundant in eukaryotic proteins, but their sequence-function relationship remains poorly understood. IDRs of transcription factors (TFs) can direct promoter selection and recruit coactivators, as shown for the budding yeast TF Msn2. To examine how IDRs encode both these functions, we compared genomic binding specificity, coactivator recruitment, and gene induction amongst a large set of designed Msn2-IDR mutants. We find that both functions depend on multiple regions across the > 600AA IDR. Yet, transcription activity was readily disrupted by mutations that showed no effect on the Msn2 binding specificity. Our data attribute this differential sensitivity to the integration of a relaxed, composition-based code directing binding specificity with a more stringent, motif-based code controlling the recruitment of coactivators and transcription activity. Therefore, Msn2 utilizes interwoven sequence grammars for encoding multiple functions, suggesting a new IDR design paradigm of potentially general use.

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Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (RNA-Seq)

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

Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (ChEC-seq)

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Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

Project description:Intrinsically disordered regions of the Msn2 transcription factor encode multiple functions using interwoven sequence grammars

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Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (ChEC-seq)

Project description:Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (ChEC-seq)

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Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (RNA-Seq)

Project description:Intrinsically disordered regions of transcription factor encode multiple functions using interwoven sequence grammars (RNA-Seq)

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Sequence heuristics to encode phase behaviour in intrinsically disordered protein polymers.

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.

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Sequence complexity of amyloidogenic regions in intrinsically disordered human proteins.

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.

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How do intrinsically disordered protein regions encode a driving force for liquid-liquid phase separation?

Project description:Liquid-liquid phase separation is the mechanism underlying the formation of biomolecular condensates. Disordered protein regions often drive phase separation, but the molecular interactions mediating this phenomenon are not well understood, sometimes leading to the conflation that all disordered protein regions drive phase separation. Given the critical role of phase separation in many cellular processes, and that dysfunction of phase separation can lead to debilitating diseases, it is important that we understand the interactions and sequence properties underlying phase behavior. A conceptual framework that divides IDRs into interacting and solvating regions has proven particularly useful, and analytical instantiations and coarse-grained models can test our understanding of the driving forces against experimental phase behavior. Validated simulation paradigms enable the exploration of sequence space to help our understanding of how disordered protein regions can encode phase behavior, which IDRs may mediate phase separation in cells, and which IDRs are highly soluble.

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