A retroelement-derived mammalian Arc protein exhibits selective RNA recognition and nucleic acid chaperone functions

Activity-regulated cytoskeleton-associated protein (Arc) is an RNA-binding protein that serves as a central hub for neuronal interactions. It is essential for intercellular signaling and contributes to synaptic plasticity, memory formation, and postnatal cortical development. Arc contains Gag-like sequences of the Ty3/Gypsy family retrotransposons and retains the ability to self-assemble into capsid-like structures carrying Arc mRNA between cells. Here, we employ an integrative approach to comprehensively dissect the RNA-binding properties of rat Arc. Based on RNA binding assays, SHAPE-MaP structural profiling, and advanced computational workflows, we find that Arc can specifically recognize its mRNA via binding to the conserved sequences in the 5' part of the coding region. Structural analysis revealed that Arc binding is guided by RNA structure, occurring preferentially near highly stable and solvent-exposed helices. Using a truncated protein variant and modeling of protein-RNA complexes, we show that the interactions with RNA are mediated by both the matrix-like and capsid-like domains of Arc. We also provide evidence that Arc possesses nucleic acid chaperone activity. The presented data elucidate the Arc mRNA encapsulation mechanism and are helpful for the potential therapeutic application of Arc capsids.