A disordered region controls cBAF activity via condensation and partner recruitment

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

doi:10.1016/j.cell.2023.08.032

A disordered region controls cBAF activity via condensation and partner recruitment

Cell. 2023 Oct 26;186(22):4936-4955.e26. doi: 10.1016/j.cell.2023.08.032. Epub 2023 Oct 3.

Authors

Ajinkya Patil¹, Amy R Strom², Joao A Paulo³, Clayton K Collings⁴, Kiersten M Ruff⁵, Min Kyung Shinn⁵, Akshay Sankar⁴, Kasey S Cervantes⁴, Tobias Wauer⁶, Jessica D St Laurent⁷, Grace Xu⁴, Lindsay A Becker², Steven P Gygi³, Rohit V Pappu⁵, Clifford P Brangwynne⁸, Cigall Kadoch⁹

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Program in Virology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
³ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁴ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, USA.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA; Howard Hughes Medical Institute, Chevy Chase, MD 21044, USA; Omenn-Darling Bioengineering Institute, Princeton University, Princeton, NJ 08544, USA. Electronic address: cbrangwy@princeton.edu.
⁹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Chevy Chase, MD 21044, USA. Electronic address: cigall_kadoch@dfci.harvard.edu.

PMID: 37788668
PMCID: PMC10792396 (available on 2024-10-26)
DOI: 10.1016/j.cell.2023.08.032

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.

Keywords: ARID1A; ARID1B; ATP-dependent chromatin remodeling; IDRs; cBAF complexes; condensates; intrinsically disordered regions; mammalian SWI/SNF complexes; phase separation; transcription factors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Chromatin
Chromatin Assembly and Disassembly*
DNA-Binding Proteins / chemistry
Humans
Intrinsically Disordered Proteins / genetics
Multiprotein Complexes* / chemistry
Multiprotein Complexes* / metabolism
Nuclear Proteins* / metabolism
Transcription Factors / metabolism

Substances

ARID1B protein, human
BANF1 protein, human
Chromatin
DNA-Binding Proteins
Intrinsically Disordered Proteins
Nuclear Proteins
Transcription Factors
Multiprotein Complexes

Abstract

Publication types

MeSH terms

Substances

Grants and funding