Nuclear speckles organisation by multi-domain RNA binding proteins as block copolymers
The phase behaviour of multi-domain proteins can be driven by specific patterns of inter-domain interactions among the folded domains and intrinsically disordered regions (IDRs). The nuclear speckle-associated serine/arginine-rich splicing factors (SRSFs) are RNA binding proteins with one or two pairs of folded RNA recognition motifs and IDRs with characteristic serine/arginine repeats. We find that the SRSF family proteins are a unique archetype of block copolymers with attractive RRM-IDR interactions and repulsive RRM-RRM and IDR-IDR interactions. The interplay of these interactions drives microphase separation of SRSF1 and the formation of ordered, size-limited assemblies of 23-45 nm in diameter, each comprising tens of molecules. The cognate long non-coding RNA, MALAT1, promotes SRSF1 microphase separation and regulates SRSF1 interactions with coding regions towards a model for the role of SRSF1 condensates in facilitating co-transcriptional splicing of pre-mRNA.