Interaction modulation through arrays of clustered methyl-arginine protein modifications

Systematic analysis of human arginine methylation identifies two distinct signaling modes; either isolated modifications akin to canonical PTM regulation, or clustered arrays within disordered protein sequence. Hundreds of proteins contain these methyl-arginine arrays and are more prone to accumulate mutations and more tightly expression-regulated than dispersed methylation targets. Arginines within an array in the highly methylated RNA binding protein SYNCRIP were experimentally shown to function in concert providing a tunable protein interaction interface. Quantitative immuno-precipitation assays defined two distinct cumulative binding mechanisms operating across 18 proximal arginine-glycine (RG) motifs in SYNCRIP. Functional binding to the methyl-transferase PRMT1 was promoted by continual arginine stretches while interaction with the methyl-binding protein SMN1 was arginine content dependent irrespective of linear position within the unstructured region. This study highlights how highly-repetitive modifiable amino acid arrays in low structural complexity regions can provide regulatory platforms, with SYNCRIP as an extreme example how arginine methylation leverages these disordered sequences to mediate cellular interactions.