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

## TL;DR

This study reveals how the ARC protein interacts with RNA, showing it can selectively bind and reshape RNA structures, which is important for neuronal communication.

## Contribution

The paper presents the first detailed in vitro analysis of ARC-RNA interactions and identifies specific RNA motifs and domains involved in binding.

## Key findings

- ARC binds RNA through specific GC-rich motifs and near stable helices in the 5′ region of Arc mRNA.
- Positively charged regions of ARC's matrix and capsid domains enhance RNA binding cooperativity.
- ARC functions as a nucleic acid chaperone, destabilizing RNA structures locally.

## Abstract

Activity-regulated cytoskeleton-associated protein (ARC) is an RNA-binding protein that also serves as a central hub for neuronal protein–protein interactions. It is essential for intercellular signaling and contributes to synaptic plasticity. ARC includes Gag-like sequences of Ty3/Gypsy retrotransposons and retains the ability to self-assemble into capsid-like structures containing Arc mRNA. Here, we employ an integrative approach to provide the first detailed in vitro analysis of ARC–RNA interactions. Using quantitative binding assays, RNA structure mapping, and ribonucleoprotein (RNP) footprinting, complemented by extensive computational analyses, we identified Arc mRNA regions specifically and non-specifically bound by ARC, as well as ARC amino acid residues involved in RNA interactions. We show that ARC recognizes RNA sequence and structure. A specific GC-rich motif is common to all bound RNA sequences, and the binding preferentially occurs near highly stable, solvent-exposed helices in the 5′ region of Arc mRNA. Surprisingly, the conserved coding sequence seems more relevant to binding specificity than the 5′-untranslated region. Our predictions suggest that ARC binding to RNA through positively charged regions of matrix and capsid domains exposes an oligomerization motif, enhancing binding cooperativity. We also provide evidence that ARC acts as a nucleic acid chaperone and can locally destabilize Arc mRNA structure.

Graphical Abstract