# Asymmetric coevolution of the MEK–ERK binding interface

## TL;DR

This study shows how the MEK–ERK protein complex evolves asymmetrically, with MEK's docking site adapting more than ERK, affecting signaling and evolution.

## Contribution

The study reveals asymmetric coevolution in the MEK–ERK interface, showing how MEK's adaptable motif balances conservation and signaling adaptability.

## Key findings

- MEK's N-terminal docking motif (D-site) shows accelerated divergence compared to the highly conserved ERK.
- Five conserved D-site residues form stable interactions with ERK’s D-recruitment site, essential for signaling.
- The D-site is conserved within species groups but diverges across them, balancing function and adaptability.

## Abstract

The highly conserved extracellular signal–regulated kinase (ERK) regulates diverse cellular processes by phosphorylating a wide range of intracellular substrates. Its catalytic activity relies on phosphorylation by a single upstream kinase, mitogen-activated protein kinase kinase (MEK), which interacts with only a few binding partners. Here, we test whether the asymmetry in protein–protein interaction network architecture influences the coevolution of the MEK–ERK complex. Phylogenetic sequence analysis across metazoan species revealed accelerated divergence in MEK’s intrinsically disordered N-terminal docking motif (docking site [D-site]), whereas ERK remained highly conserved. Structure prediction with AlphaFold2 and extensive molecular dynamics simulations showed that five conserved D-site residues form stable hydrophobic and electrostatic contacts with ERK’s D-recruitment site. Functional assays in Drosophila melanogaster confirmed that these D-site interactions are essential for proper downstream signaling and support an allosteric role for this motif. Our results demonstrate that MEK uses a structurally simple yet evolutionarily adaptable motif to regulate MEK–ERK complex stability and binding dynamics. The D-site is strongly conserved within phylogenetic groups such as insects or terrestrial vertebrates, yet diverges across them, reflecting evolutionary pressures that balance functional conservation with signaling adaptability. The presented approach illustrates how the combined approach using sequencing data, molecular simulations, and targeted perturbations can be used to address fundamental questions about the evolution of protein–protein interaction networks.