A Disordered Region Controls CBAF Activity Via Condensation and Partner Recruitment

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Oct 3

PMID 37788668

Authors

Ajinkya Patil

Amy R Strom

Joao A Paulo

Clayton K Collings

Kiersten M Ruff

Min Kyung Shinn

Akshay Sankar

Kasey S Cervantes

Tobias Wauer

Jessica D St Laurent

Grace Xu

Lindsay A Becker

Steven P Gygi

Rohit V Pappu

Clifford P Brangwynne

Cigall Kadoch

Affiliations

Soon will be listed here.

Abstract

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 that condensate formation and heterotypic interactions are distinct and separable features of an IDR within the ARID1A/B subunits of the mSWI/SNF chromatin remodeler, cBAF, and establish distinct "sequence grammars" underlying each contribution. Condensation is driven by uniformly distributed tyrosine residues, and partner interactions are mediated by non-random blocks rich in alanine, glycine, and glutamine residues. These features concentrate a specific cBAF protein-protein interaction network and are essential for chromatin localization and activity. Importantly, human disease-associated perturbations in ARID1B IDR sequence grammars disrupt cBAF function in cells. Together, these data identify IDR contributions to chromatin remodeling and explain how phase separation provides a mechanism through which both genomic localization and functional partner recruitment are achieved.

Citing Articles

Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars.

Hoffmann C, Ruff K, Edu I, Shinn M, Tromm J, King M J Mol Biol. 2025; 437(8):168987.

PMID: 39947282 PMC: 11903162. DOI: 10.1016/j.jmb.2025.168987.

VEGFR3 mitigates hypertensive nephropathy by enhancing mitophagy via regulating crotonylation of HSPA1L.

Wu Q, Fu J, Zhu B, Meng W, Ma J, Lv Y Cell Commun Signal. 2025; 23(1):52.

PMID: 39875989 PMC: 11773936. DOI: 10.1186/s12964-025-02045-x.

Impact of frequent ARID1A mutations on protein stability provides insights into cancer pathogenesis.

Goutam R, Huang G, Medina E, Ding F, Edenfield W, Sanabria H Sci Rep. 2025; 15(1):3072.

PMID: 39856215 PMC: 11760938. DOI: 10.1038/s41598-025-87103-7.

Molecular determinants of condensate composition.

Holehouse A, Alberti S Mol Cell. 2025; 85(2):290-308.

PMID: 39824169 PMC: 11750178. DOI: 10.1016/j.molcel.2024.12.021.

Basic Epigenetic Mechanisms.

Davie J, Sattarifard H, Sudhakar S, Roberts C, Beacon T, Muker I Subcell Biochem. 2025; 108():1-49.

PMID: 39820859 DOI: 10.1007/978-3-031-75980-2_1.

References

Oates M, Romero P, Ishida T, Ghalwash M, Mizianty M, Xue B . D²P²: database of disordered protein predictions. Nucleic Acids Res. 2012; 41(Database issue):D508-16. PMC: 3531159. DOI: 10.1093/nar/gks1226. View

Sherry K, Das R, Pappu R, Barrick D . Control of transcriptional activity by design of charge patterning in the intrinsically disordered RAM region of the Notch receptor. Proc Natl Acad Sci U S A. 2017; 114(44):E9243-E9252. PMC: 5676888. DOI: 10.1073/pnas.1706083114. View

Kadoch C, Hargreaves D, Hodges C, Elias L, Ho L, Ranish J . Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013; 45(6):592-601. PMC: 3667980. DOI: 10.1038/ng.2628. View

Huerta-Cepas J, Szklarczyk D, Heller D, Hernandez-Plaza A, Forslund S, Cook H . eggNOG 5.0: a hierarchical, functionally and phylogenetically annotated orthology resource based on 5090 organisms and 2502 viruses. Nucleic Acids Res. 2018; 47(D1):D309-D314. PMC: 6324079. DOI: 10.1093/nar/gky1085. View

Holehouse A, Das R, Ahad J, Richardson M, Pappu R . CIDER: Resources to Analyze Sequence-Ensemble Relationships of Intrinsically Disordered Proteins. Biophys J. 2017; 112(1):16-21. PMC: 5232785. DOI: 10.1016/j.bpj.2016.11.3200. View

Elias J, Gygi S . Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods. 2007; 4(3):207-14. DOI: 10.1038/nmeth1019. View

Bremer A, Farag M, Borcherds W, Peran I, Martin E, Pappu R . Deciphering how naturally occurring sequence features impact the phase behaviours of disordered prion-like domains. Nat Chem. 2021; 14(2):196-207. PMC: 8818026. DOI: 10.1038/s41557-021-00840-w. View

Gatchalian J, Malik S, Ho J, Lee D, Kelso T, Shokhirev M . A non-canonical BRD9-containing BAF chromatin remodeling complex regulates naive pluripotency in mouse embryonic stem cells. Nat Commun. 2018; 9(1):5139. PMC: 6277444. DOI: 10.1038/s41467-018-07528-9. View

Kar M, Dar F, Welsh T, Vogel L, Kuhnemuth R, Majumdar A . Phase-separating RNA-binding proteins form heterogeneous distributions of clusters in subsaturated solutions. Proc Natl Acad Sci U S A. 2022; 119(28):e2202222119. PMC: 9282234. DOI: 10.1073/pnas.2202222119. View

10.

Nott T, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A . Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell. 2015; 57(5):936-947. PMC: 4352761. DOI: 10.1016/j.molcel.2015.01.013. View

11.

Mashtalir N, DAvino A, Michel B, Luo J, Pan J, Otto J . Modular Organization and Assembly of SWI/SNF Family Chromatin Remodeling Complexes. Cell. 2018; 175(5):1272-1288.e20. PMC: 6791824. DOI: 10.1016/j.cell.2018.09.032. View

12.

Bogershausen N, Wollnik B . Mutational Landscapes and Phenotypic Spectrum of SWI/SNF-Related Intellectual Disability Disorders. Front Mol Neurosci. 2018; 11:252. PMC: 6085491. DOI: 10.3389/fnmol.2018.00252. View

13.

Zhu Q, Liu N, Orkin S, Yuan G . CUT&RUNTools: a flexible pipeline for CUT&RUN processing and footprint analysis. Genome Biol. 2019; 20(1):192. PMC: 6734249. DOI: 10.1186/s13059-019-1802-4. View

14.

Elias J, Gygi S . Target-decoy search strategy for mass spectrometry-based proteomics. Methods Mol Biol. 2009; 604:55-71. PMC: 2922680. DOI: 10.1007/978-1-60761-444-9_5. View

15.

Michel B, DAvino A, Cassel S, Mashtalir N, McKenzie Z, McBride M . A non-canonical SWI/SNF complex is a synthetic lethal target in cancers driven by BAF complex perturbation. Nat Cell Biol. 2018; 20(12):1410-1420. PMC: 6698386. DOI: 10.1038/s41556-018-0221-1. View

16.

Santen G, Kriek M, van Attikum H . SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics. 2012; 7(11):1219-24. PMC: 3499322. DOI: 10.4161/epi.22299. View

17.

Ramirez F, Ryan D, Gruning B, Bhardwaj V, Kilpert F, Richter A . deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016; 44(W1):W160-5. PMC: 4987876. DOI: 10.1093/nar/gkw257. View

18.

Kuhn R, Haussler D, Kent W . The UCSC genome browser and associated tools. Brief Bioinform. 2012; 14(2):144-61. PMC: 3603215. DOI: 10.1093/bib/bbs038. View

19.

Strom A, Emelyanov A, Mir M, Fyodorov D, Darzacq X, Karpen G . Phase separation drives heterochromatin domain formation. Nature. 2017; 547(7662):241-245. PMC: 6022742. DOI: 10.1038/nature22989. View

20.

Shinn M, Cohan M, Bullock J, Ruff K, Levin P, Pappu R . Connecting sequence features within the disordered C-terminal linker of FtsZ to functions and bacterial cell division. Proc Natl Acad Sci U S A. 2022; 119(42):e2211178119. PMC: 9586301. DOI: 10.1073/pnas.2211178119. View