Specific catalytically impaired DDX3X mutants form sexually dimorphic hollow condensates

• Published in: Nature communications Vol. 15; no. 1; pp. 9553 - 17
• Main Authors: Owens, Michael C., Shen, Hui, Yanas, Amber, Mendoza-Figueroa, Maria Saraí, Lavorando, Ellen, Wei, Xiaoyu, Shweta, Him, Tang, Hsin-Yao, Goldman, Yale E., Liu, Kathy Fange
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.11.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/33; 14/63; 38; 38/91; 631/45/173; 631/45/500; 82/83; Bias; Condensates; DNA helicase; Dynamic structural analysis; Humanities and Social Sciences; multidisciplinary; Mutants; Neurodevelopmental disorders; Proteomics; RNA helicase; Science; Science (multidisciplinary); Sexual dimorphism; Unwinding
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-53636-0

Mutations in the RNA helicase DDX3X, implicated in various cancers and neurodevelopmental disorders, often impair RNA unwinding and translation. However, the mechanisms underlying the impairment and the differential interactions of DDX3X mutants with wild-type (WT) X-linked DDX3X and Y-linked homolog DDX3Y remain elusive. This study reveals that specific DDX3X mutants more frequently found in disease form distinct hollow condensates in cells. Using a combined structural, biochemical, and single-molecule microscopy study, we show that reduced ATPase and RNA release activities contribute to condensate formation and these catalytic deficits result from inhibiting the catalytic cycle at multiple steps. Proteomic investigations further demonstrate that these hollow condensates sequester WT DDX3X/DDX3Y and other proteins crucial for diverse signaling pathways. WT DDX3X enhances the dynamics of heterogeneous mutant/WT hollow condensates more effectively than DDX3Y. These findings offer valuable insights into the catalytic defects of specific DDX3X mutants and their differential interactions with wild-type DDX3X and DDX3Y, potentially explaining sex biases in disease. Here the authors find that DDX3X mutants with catalytic impairments form hollow condensates in cells that have slower dynamics when co-condensed with DDX3Y than with WT DDX3X, revealing potential mechanisms of sex biases in DDX3X-related diseases.