# Specificity of the stabilizing interaction between intrinsically disordered protein sequences and G-quadruplexes in RNA

## TL;DR

This study shows how disordered protein regions selectively stabilize RNA G-quadruplexes, revealing a new mechanism for RNA folding and recognition.

## Contribution

The paper identifies how specific amino acid and nucleotide identities drive selective interactions between RGG peptides and RNA G-quadruplexes.

## Key findings

- The RGG domain selectively stabilizes the human telomeric TERRA rG4 without high-affinity binding or cations.
- NMR and CD spectroscopy reveal that individual nucleotide and amino acid identities determine interaction specificity.
- The findings explain how IDRs can selectively recognize RNA over DNA G4s and the high mutation frequency in IDRs.

## Abstract

Intrinsically disordered regions (IDRs) are present in and essential for the function of nearly all the proteins involved in regulation, cell, and developmental processes. The RGG domain in IDRs binds ‘promiscuously’ to RNA G-quadruplexes (rG4s), a non-canonical 4-stranded secondary structure that occurs in many transcripts involved in gene regulation. Here we show, using weak binding interactions between a minimal RGG-rich peptide and rG4s, that the IDR selectively templates and stabilizes the structure of the human telomeric TERRA rG4, providing a unique pathway to RNA folding that does not rely on high-affinity binding or monovalent cations. Multidimensional NMR and circular dichroism (CD) spectroscopy analyses reveal individual nucleotide and amino acid identities determine the specificity of the interaction between RGG peptides and rG4s, explaining how IDRs can selectively recognize RNA over DNA G4s, the high specificity of such interactions in vivo, and the high frequency of monogenic mutations observed in IDRs.

Graphical Abstract