Přehled o publikaci

The precise organization of biomolecular condensates is required for viral replication1. Various cellular components make up these condensates, including proteins, molecules, and nucleic acids. The individual interactions of these components and their local concentrations dictate the internal organization. Viruses can create condensates of their own or introduce new components to pre-existing ones in the host cell2. Biophysical understanding of this process allows for the rational design of condensate control mechanisms. For viral applications, there are three areas of interest. The first is maturation, where the liquid-like properties are arrested due to strong interactions, trapping components within the condensate. The second is dissolution where condensates are unable to form a dense phase. The third is compositional control, where individual components can be removed from condensates. Here we show computational approaches that can define the interaction network within condensates and allow us to control them. We focus on leveraging interactions between multi-domain proteins in condensates. Intrinsically disordered regions facilitate separation into a protein dense and dilute phase3. However, globular regions can also enhance phase separation and are easier targets for drug delivery. Initial work was done on the two-component system of RECQL5 and RNA-Polymerase II (RNAPII). These two proteins interact during transcription, a process which can be hijacked by viruses4. We isolated the three distinct domains of RECQL5 responsible for the condensate formation, both in vitroand in silico. A schematic description can be seen in Figure 1. Three types of interaction are present (1) globular-globular (2) disordered-disordered (3) globular-disordered. Each interaction exhibits control over different organization stages. The disordered interactions localize RECQL5, the globular-disordered interactions recruit RNAPII, and the globular interactions slow transcription. So far, we have interrupted these mechanisms through domain removal. However, we next move towards using peptides and drug molecules to exercise condensate control. We further extend these tools and methods to 228 other multi-domain proteins involved in genomic maintenance.