2023-10-06 プリンストン大学
◆IDRは、特定の相互作用を通じて細胞内で生体分子を集めるための液滴を形成し、細胞活動をサポートします。特に、がんと神経発達障害に関連する変異がIDRに与える影響が研究され、細胞プロセスの異常を理解し、新しい治療戦略の基盤となる可能性が示唆されています。
◆この研究は、IDRが細胞生物学において中心的な役割を果たすことを初めて示し、新たな洞察を提供します。
<関連情報>
- https://engineering.princeton.edu/news/2023/10/06/overlooked-parts-proteins-revealed-critical-fundamental-functions-life
- https://www.cell.com/cell/fulltext/S0092-8674(23)00965-0
cBAFの活性を制御する無秩序領域が、凝縮とパートナーのリクルートメントを介して機能していることが明らかになった 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
Cell Published:October 02, 2023
DOI:https://doi.org/10.1016/j.cell.2023.08.032
Highlights
•A disordered region of ARID1A/B cBAF subunits controls condensation and interactions
•cBAF targeting and activity require phase separation and functional partner recruitment
•Sequence patterning analysis uncouples grammar of self- and non-self-interactions
•Disease-associated IDR mutations disrupt protein interactions and genomic targeting
Summary
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.
