Interaction modulation through arrays of clustered methyl-arginine protein modifications

Systematic analysis of human arginine methylation events bifurcates its signaling mechanism, functioning either in isolation akin to canonical PTM regulation or clustered within disordered protein sequence. Hundreds of proteins contain methyl-arginine clusters and are more prone to mutation and more tightly expression-regulated than dispersed methylation targets. Arginine clusters 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 regulatory mechanisms operating across 18 proximal arginine-glycine 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 di-amino acid motifs in otherwise low structural complexity regions can provide regulatory potential, and with SYNCRIP as an extreme example how PTMs leverage these disordered sequences to drive cellular functions.