A disordered region controls cBAF activity via condensation and partner recruitment.

Autor:	Patil A; 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., Strom AR; Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA., Paulo JA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Collings CK; 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., Ruff KM; Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, USA., Shinn MK; Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, USA., Sankar A; 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., Cervantes KS; 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., Wauer T; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA., St Laurent JD; 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., Xu G; 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., Becker LA; Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA., Gygi SP; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA., Pappu RV; Department of Biomedical Engineering and Center for Biomolecular Condensates, Washington University in St. Louis, St. Louis, MO 63130, USA., Brangwynne CP; 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., Kadoch C; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Oct 26; Vol. 186 (22), pp. 4936-4955.e26. Date of Electronic Publication: 2023 Oct 03.
DOI:	10.1016/j.cell.2023.08.032
Abstrakt:	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. Competing Interests: Declaration of interests C.K. is the scientific founder, Scientific Advisor to the Board of Directors, Scientific Advisory Board member, shareholder, and consultant for Foghorn Therapeutics. C.K. also serves on the Scientific Advisory Boards of Nereid Therapeutics (shareholder and consultant), Nested Therapeutics (shareholder and consultant), Accent Therapeutics (shareholder and consultant), and Fibrogen (consultant) and is a consultant for Cell Signaling Technologies and Google Ventures (shareholder and consultant). C.P.B. is a scientific founder, Scientific Advisory Board member, shareholder, and consultant for Nereid Therapeutics. R.V.P. is a member of the Scientific Advisory Board for Dewpoint Therapeutics (shareholder and consultant). The authors have submitted a patent application related to this work. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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