Diffusion of a disordered protein on its folded ligand

Intrinsically disordered proteins often form dynamic complexes with their ligands. Yet, the speed and amplitude of these motions are hidden in classical binding kinetics. Here, we directly measure the dynamics in an exceptionally mobile, high-affinity complex. We show that the disordered tail of the cell adhesion protein E-cadherin dynamically samples a large surface area of the protooncogene beta-catenin. Single-molecule experiments and molecular simulations resolve these motions with high resolution in space and time. Contacts break and form within hundreds of microseconds without a dissociation of the complex. The energy landscape of this complex is rugged with many small barriers (3 to 4 kBT) and reconciles specificity, high affinity, and extreme disorder. A few persistent contacts provide specificity, whereas unspecific interactions boost affinity.

Automated summary

Intrinsically disordered proteins form dynamic complexes with their ligands, with motions hidden in classical binding kinetics. By directly measuring dynamics in a highly mobile, high-affinity complex, researchers found that the energy landscape of the complex is rugged with small barriers reconciling specificity, high affinity, and extreme disorder. Single-molecule experiments and molecular simulations provide high resolution in space and time for resolving these motions.