A disordered region controls cBAF activity via condensation and partner recruitment

Cell, Год журнала: 2023, Номер 186(22), С. 4936 - 4955.e26

Опубликована: Окт. 1, 2023

Intrinsically disordered regions (IDRs) represent a large percentage of overall nuclear protein content. The prevailing dogma is that IDRs engage in non-specific interactions because they are poorly constrained by evolutionary selection. Here, we demonstrate condensate formation and heterotypic distinct separable features an IDR within the ARID1A/B subunits mSWI/SNF chromatin remodeler, cBAF, establish "sequence grammars" underlying each contribution. Condensation driven uniformly distributed tyrosine residues, partner mediated non-random blocks rich alanine, glycine, glutamine residues. These concentrate specific cBAF protein-protein interaction network essential for localization activity. Importantly, human disease-associated perturbations ARID1B sequence grammars disrupt function cells. Together, these data identify contributions to remodeling explain how phase separation provides mechanism through which both genomic functional recruitment achieved.

Язык: Английский

---

Enhancer selectivity in space and time: from enhancer–promoter interactions to promoter activation

Nature Reviews Molecular Cell Biology, Год журнала: 2024, Номер 25(7), С. 574 - 591

Опубликована: Фев. 27, 2024

Язык: Английский

---

Disordered regions of condensate-promoting proteins have distinct molecular signatures associated with cellular function

Journal of Molecular Biology, Год журнала: 2025, Номер unknown, С. 168953 - 168953

Опубликована: Янв. 1, 2025

Язык: Английский

---

Updated protein domain annotation of the PARP protein family sheds new light on biological function

Nucleic Acids Research, Год журнала: 2023, Номер 51(15), С. 8217 - 8236

Опубликована: Июнь 3, 2023

AlphaFold2 and related computational tools have greatly aided studies of structural biology through their ability to accurately predict protein structures. In the present work, we explored AF2 models 17 canonical members human PARP family supplemented this analysis with new experiments an overview recent published data. proteins are typically involved in modification nucleic acids mono or poly(ADP-ribosyl)ation, but function can be modulated by presence various auxiliary domains. Our provides a comprehensive view structured domains long intrinsically disordered regions within PARPs, offering revised basis for understanding these proteins. Among other functional insights, study model PARP1 domain dynamics DNA-free DNA-bound states enhances connection between ADP-ribosylation RNA ubiquitin-like modifications predicting putative RNA-binding E2-related RWD certain PARPs. line bioinformatic analysis, demonstrate first time PARP14's capability activity vitro. While our insights align existing experimental data probably accurate, they need further validation experiments.

Язык: Английский

---

Revolutionizing protein–protein interaction prediction with deep learning

Current Opinion in Structural Biology, Год журнала: 2024, Номер 85, С. 102775 - 102775

Опубликована: Фев. 7, 2024

Язык: Английский

---

An autoinhibitory switch of the LSD1 disordered region controls enhancer silencing

Molecular Cell, Год журнала: 2024, Номер 84(12), С. 2238 - 2254.e11

Опубликована: Июнь 1, 2024

Язык: Английский

---

Biomolecular condensation of human IDRs initiates endogenous transcription via intrachromosomal looping or high-density promoter localization

Nucleic Acids Research, Год журнала: 2025, Номер 53(4)

Опубликована: Янв. 22, 2025

Protein intrinsically disordered regions (IDRs) are critical gene-regulatory components and aberrant fusions between IDRs DNA-binding/chromatin-associating domains cause diverse human cancers. Despite this importance, how influence gene expression, IDR fusion proteins provoke oncogenesis, remains incompletely understood. Here we develop a series of synthetic dCas9-IDR to establish that locus-specific recruitment can be sufficient stimulate endogenous expression. Using dCas9 fused the paradigmatic leukemogenic NUP98 IDR, also demonstrate activate transcription via localized biomolecular condensation in manner is dependent upon overall concentration, local binding density, amino acid composition. To better clarify oncogenic role IDRs, construct clinically observed show that, while generally non-overlapping, NUP98-IDR convergently drive core expression program donor-derived hematopoietic stem cells. Interestingly, find leukemic arises through differing mechanistic routes based partner; either distributed intragenic intrachromosomal looping, or dense at promoters. Altogether, our studies roles and, for connect capacity pathological cellular programs, creating potential opportunities generalized mechanistically tailored therapies.

Язык: Английский

---

Flanking regions, amyloid cores, and polymorphism: the potential interplay underlying structural diversity

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(9), С. 105122 - 105122

Опубликована: Авг. 1, 2023

The β-sheet-rich amyloid core is the defining feature of protein aggregates associated with neurodegenerative disorders. Recent investigations have revealed that there exist multiple examples same protein, sequence, forming a variety cores distinct structural characteristics. These variants, termed as polymorphs, are hypothesized to influence pathological profile and progression different diseases, giving rise unique phenotypic differences. Thus, identifying origin properties these variants remain focus studies, preliminary step in development therapeutic strategies. Here, we review potential role flanking regions inducing polymorphism. regions, adjacent cores, show preponderance for being structurally disordered, imbuing them functional promiscuity. dynamic nature can then manifest form conformational polymorphism aggregates. We take closer look at sequences followed by polymorphic well-characterized proteins amyloid-β, α-synuclein, Tau, TDP-43. also consider factors potentially aggregate structure how be viewed novel targets strategies utilizing their properties.

Язык: Английский

---

An intrinsically disordered region controlling condensation of a circadian clock component and rhythmic transcription in the liver

Molecular Cell, Год журнала: 2023, Номер 83(19), С. 3457 - 3469.e7

Опубликована: Окт. 1, 2023

Язык: Английский

---

High-throughput affinity measurements of direct interactions between activation domains and co-activators

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Авг. 20, 2024

Abstract Sequence-specific activation by transcription factors is essential for gene regulation 1,2 . Key to this are domains, which often fall within disordered regions of 3,4 and recruit co-activators initiate 5 These interactions difficult characterize via most experimental techniques because they typically weak transient 6,7 Consequently, we know very little about whether these promiscuous or specific, the mechanisms binding, how tune strength activation. To address questions, developed a microfluidic platform expression purification hundreds domains in parallel followed direct measurement co-activator binding affinities (STAMMPPING, Simultaneous Trapping Affinity Measurements Microfluidic Protein-Protein INteraction Generator). By applying STAMMPPING quantify between eight 204 human (>1,500 K d s), provide first quantitative map reveal 334 novel pairs. We find that metazoan-specific P300 directly binds >100 potentially explaining its widespread recruitment across genome influence transcriptional Despite sharing similar molecular properties ( e.g. enrichment negative hydrophobic residues), utilize distinct biophysical certain domains. Co-activator domain affinity occupancy well-predicted analytical models account multivalency, vitro quantitatively predict cells with an ultrasensitive response. Not only do our results demonstrate ability measure even protein-protein high throughput, but also necessary resource over 1,500 domain/co-activator lays foundation understanding basis

Язык: Английский

---