Diffusion of a disordered protein on its folded ligand

Area of Science:

• Biochemistry and Molecular Biology
• Structural Biology
• Protein Dynamics

Background:

• Intrinsically disordered proteins (IDPs) are crucial in cellular processes, often forming dynamic complexes.
• Classical binding kinetics obscure the rapid motions within these IDP-ligand interactions.
• Understanding IDP dynamics is key to elucidating their functions in high-affinity binding.

Purpose of the Study:

• To directly measure the dynamics of an exceptionally mobile, high-affinity protein complex.
• To resolve the spatial and temporal resolution of motions in intrinsically disordered protein complexes.
• To investigate the energy landscape and reconcile specificity, affinity, and disorder in protein interactions.

Main Methods:

• Single-molecule experiments to observe protein dynamics in real-time.
• Molecular simulations to provide high-resolution insights into protein motions.
• Analysis of contact formation and breakage within protein complexes.

Main Results:

• The disordered tail of E-cadherin dynamically samples a large surface area of β-catenin.
• Protein contacts break and reform within hundreds of microseconds without complex dissociation.
• The energy landscape features numerous small barriers (3-4 kBT), balancing specificity and affinity.
• Persistent contacts confer specificity, while unspecific interactions enhance affinity.

Conclusions:

• Direct measurement reveals the dynamic nature of intrinsically disordered protein complexes.
• A rugged energy landscape with small barriers explains the simultaneous high affinity, specificity, and disorder.
• This dynamic interaction model provides a new framework for understanding IDP functions in cellular adhesion and signaling.