Deciphering disordered regions controlling mRNA decay in high-throughput

Abstract

Intrinsically disordered regions within proteins drive specific molecular functions despite lacking a defined structure^1,2. Although disordered regions are integral to controlling mRNA stability and translation, the mechanisms underlying these regulatory effects remain unclear³. Here we reveal the molecular determinants of this activity using high-throughput functional profiling. Systematic mutagenesis across hundreds of regulatory disordered elements, combined with machine learning, reveals a complex pattern of molecular features important for their activity. The presence and arrangement of aromatic residues strongly predicts the ability of seemingly diverse protein sequences to influence mRNA stability and translation. We further show how many of these regulatory elements exert their effects by engaging core mRNA decay machinery. Our results define molecular features and biochemical pathways that explain how disordered regions control mRNA expression and shed light on broader principles within functional, unstructured proteins.