Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins.

Area of Science:

• Biochemistry and Molecular Biology
• Evolutionary Biology
• Structural Biology

Background:

• Intrinsically disordered protein domains frequently interact with multiple partners.
• The evolution of binding affinity from low to high is plausible but poorly understood at a molecular level.
• The NCBD/CID interaction evolved from low to high affinity in vertebrate evolution.

Purpose of the Study:

• To map native contacts in the transition states of ancestral (low-affinity) and human (high-affinity) NCBD/CID interactions.
• To elucidate the molecular changes in the binding mechanism during the evolution of protein-protein interactions.
• To understand how disordered proteins adapt to new binding partners.

Main Methods:

• Comparative analysis of transition states for ancestral and human NCBD/CID complexes.
• Mapping of native contacts during protein-protein binding and folding.
• Characterization of transient interactions and protein disorder in binding pathways.

Main Results:

• The coupled binding and folding mechanisms share similarities between ancestral and human complexes.
• The ancestral complex exhibited greater native hydrophobic contact formation in its transition state.
• The human complex showed more heterogeneous transient interactions, including electrostatic pairings, and increased disorder.

Conclusions:

• Protein-protein interaction evolution involves adaptable binding mechanisms.
• Exploiting diverse transient interactions aids adaptation to new binding partners while maintaining the core binding pathway.
• Understanding these mechanisms provides insights into protein evolution and function.