Contribution of chromosome-naïve transposon-seeded network of DNA templates to intracellular pools of protein dimers of liquid-liquid phase-separated condensate-forming proteins

Abstract

Molecular mechanisms governing protein-protein interactions (PPI) contributing to the biogenesis of membraneless condensates remain poorly understood. Observations reported in this contribution demonstrate that liquid-liquid phase-separated (LLPS) condensate-forming proteins and their variants harboring condensate-disrupting human pathogenic mutations are significantly enriched among PPI cascade constituents of the Hybrid Assembly Pathway (HAP) of endogenous multiprotein complexes (EMC). In contrast, no structured or disordered proteins defined as condensate-negative molecules were detected among PPI cascade constituents. Cumulative evidence derived from different lines of analytical inquiries support the concept of the significant contributions of PPI cascade constituents of HAP to the biogenesis of intracellular pools of cell type-specific protein heterodimers assembled with the engagement of at least one protein monomer selected from condensate-forming protein molecules. Analytical evidence documented in this study support the concept that genome-wide chromosome-naïve networks of transposon-seeded DNA-templates nucleate the initiation of PPI cascade chain reactions with the capacity to facilitate the concurrent iterative assembly in human cells of both the membraneless biomolecular condensates and the structured multiprotein complexes. AlphaFold 3D modelling of mutation patterns and analysis of partner-bound experimental structures identified variants located at a measured protein dimerization interface. This contribution nominates numerous protein heterodimers of potential relevance to human pathophysiology for follow-up mechanistic studies of potential fundamental and translational impacts.